Zinc ionophore and use thereof

文档序号：1077698 发布日期：2020-10-16 浏览：17次中文

阅读说明：本技术 锌离子载体及其用途 (Zinc ionophore and use thereof ) 是由 M·沃克尔 C·麦科德维特 M·范艾特兹特恩 A·麦克万于 2018-10-12 设计创作，主要内容包括：本发明涉及锌(II)盐与锌离子载体的组合在恢复在先耐药性致病菌对抗生素的敏感性中的用途。还描述了使耐药性致病菌对抗生素重新敏感的方法,所述方法包括施用锌离子载体与(II)盐的组合；和治疗细菌感染的方法,所述方法包括施用锌离子载体与锌(II)盐的组合,同时和/或顺序地施用治疗有效量的抗生素。(The present invention relates to the use of a combination of a zinc (II) salt and a zinc ionophore to restore the sensitivity of previously drug resistant pathogenic bacteria to antibiotics. Also described is a method of resensitising a drug-resistant pathogen to an antibiotic, the method comprising administering a zinc ionophore in combination with (II) a salt; and methods of treating bacterial infections comprising administering a combination of a zinc ionophore and a zinc (II) salt, simultaneously and/or sequentially with a therapeutically effective amount of an antibiotic.)

1. A method of restoring the sensitivity of drug-resistant pathogenic bacteria to antibiotics comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable zinc ionophore in combination with an effective amount of a pharmaceutically acceptable zinc (II) salt or solvate thereof;

wherein the antibiotic is not an aminoglycoside antibiotic.

2. A method of treating a bacterial infection in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable derivative thereof, in combination with an effective amount of a pharmaceutically acceptable zinc (II) salt, or a pharmaceutically acceptable solvate thereof, simultaneously and/or sequentially with a therapeutically effective amount of an antibiotic, or a pharmaceutically acceptable derivative thereof;

wherein the antibiotic is not an aminoglycoside antibiotic.

3. A method of restoring the sensitivity of drug-resistant pathogenic bacteria to antibiotics comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable zinc ionophore.

4. A method of treating a bacterial infection in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable derivative thereof, simultaneously and/or sequentially and in any order, a therapeutically effective amount of an antibiotic, or a pharmaceutically acceptable derivative thereof.

5. Use of a pharmaceutically acceptable zinc ionophore in combination with a pharmaceutically acceptable zinc (II) salt or solvate thereof for restoring the sensitivity of drug-resistant pathogenic bacteria to antibiotics;

wherein the antibiotic is not an aminoglycoside antibiotic.

6. Use of a pharmaceutically acceptable zinc ionophore in combination with a pharmaceutically acceptable zinc (II) salt or solvate thereof for the inhibition of resistance of pathogenic bacteria to antibiotics;

wherein the antibiotic is not an aminoglycoside antibiotic.

7. Use of a combination of a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate thereof as an antibiotic adjuvant or antibiotic enhancer;

wherein the antibiotic is not an aminoglycoside antibiotic.

8. Use of a pharmaceutically acceptable zinc ionophore for restoring the sensitivity of drug-resistant pathogenic bacteria to antibiotics.

9. Use of a pharmaceutically acceptable zinc ionophore to inhibit resistance of pathogenic bacteria to antibiotics.

10. Use of a pharmaceutically acceptable zinc ionophore as an antibiotic adjuvant or antibiotic enhancer.

11. A pharmaceutical composition comprising a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable zinc (II) salt, or a pharmaceutically acceptable solvate thereof; and

an antibiotic or a pharmaceutically acceptable derivative thereof, wherein the antibiotic is not an aminoglycoside antibiotic; and

a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable derivative thereof, and an antibiotic, or a pharmaceutically acceptable derivative thereof; and

a pharmaceutically acceptable carrier.

13. A method of treating a bacterial infection in a subject, comprising administering a therapeutically effective and non-toxic amount of a pharmaceutical composition according to claim 11 or claim 12.

14. Use of a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable zinc (II) salt, or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for resensitising drug-resistant pathogenic bacteria to an antibiotic;

wherein the antibiotic is not an aminoglycoside antibiotic.

15. A combination of a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable zinc (II) salt, or a pharmaceutically acceptable solvate thereof, for use separately, sequentially or simultaneously and in any order with an antibiotic, or a pharmaceutically acceptable derivative thereof, in the treatment of a bacterial infection;

wherein the antibiotic is not an aminoglycoside antibiotic.

16. Use of a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable zinc (II) salt, or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of a bacterial infection, wherein the medicament is for co-administration with a non-aminoglycoside antibiotic or a pharmaceutically acceptable derivative thereof, simultaneously, sequentially or in any order.

17. The use, method or composition according to any one of claims 1 to 16, wherein the zinc ionophore is an 8-hydroxyquinoline derivative of formula (I) as defined in WO 2004/007461.

18. The use, method or composition of any of claims 1-16, wherein the zinc ionophore is a compound of formula I:

wherein R is^1aAnd R^1bIndependently H, halogen, OR^2a、SR^2a、CF₃、C_1-4Alkyl or NR^2aR^2b；R^2aAnd R^2bIndependently is H or optionally substituted C_1-4An alkyl group;

or a pharmaceutically acceptable derivative thereof;

or a compound of formula II:

wherein:

R³and R⁵Independently is H; optionally substituted C_1-6An alkyl group; optionally substituted C_2-6An alkenyl group; optionally substituted C_2-6An alkynyl group; optionally substituted C_3-6A cycloalkyl group; optionally substituted aryl; an optionally substituted heterocyclic group; CN; OR (OR)⁶、SR⁶、COR⁶、CSR⁶、HCNOR⁶Or HCNN⁶Wherein R is⁶Is H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; NR (nitrogen to noise ratio)⁸R⁹Or SO₂NR⁸R⁹Wherein R is⁸And R⁹Independently selected from H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl and optionally substituted heterocyclyl; CONR⁹R¹⁰Wherein R is⁹As defined above, andR¹⁰is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; CH (CH)₂CONR⁸R⁹Wherein R is⁸And R⁹As defined above; and (CH)₂)_nNR⁹R¹¹Wherein R is⁹As defined above, and R¹¹Selected from optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and SO₂R¹²Wherein R is¹²Is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, and n is 1-6;

R^4aand R^4bIndependently is H, optionally substituted C_1-4Alkyl or halogen;

or a pharmaceutically acceptable derivative thereof.

19. The use, method or composition of any one of claims 1-16, wherein the zinc ionophore is 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol):

5, 7-dichloro-2- [ (dimethylamino) methyl ] -8-hydroxyquinoline (PBT2):

or a pharmaceutically acceptable derivative of any one thereof.

20. The use, method or composition of any of claims 1-16, wherein the zinc (II) salt is zinc chloride, zinc acetate or zinc sulfate or a solvate of any thereof.

21. The use, method or composition of any of claims 1,2, 5-7, 11 or 13-15, wherein the zinc ionophore and the zinc (II) salt or solvate thereof is in the form of a zinc (II) coordination compound.

22. The use, method or composition of claim 21, wherein the zinc (II) coordination compound is a compound of formula VII:

Zn(II)[L]₂

wherein both L groups are the same and are the anion of the zinc ionophore of any one of claims 17 to 19;

or a pharmaceutically acceptable derivative thereof.

23. The use, method or composition of claim 22, wherein the zinc (II) coordination compound is:

or a pharmaceutically acceptable derivative thereof.

24. The use, method or composition of any one of claims 1-23, wherein said antibiotic is a carbapenem, a cephalosporin, a glycopeptide, a lincosamide, a macrolide, a monobactam, a nitrofuran, an oxazolidinone, a penicillin, a polypeptide, a quinolone, a sulfonamide or a tetracycline; or chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, thiamphenicol, tigecycline, tinidazole or trimethoprim, or a pharmaceutically acceptable derivative of any of them.

25. The use, method or composition of any one of claims 1-23, wherein the antibiotic is colistin, polymyxin B, tetracycline, tigecycline, doxycycline, oxacillin, erythromycin, ampicillin, vancomycin, penicillin or chloramphenicol, or a pharmaceutically acceptable derivative of any one thereof.

26. The use, method or composition according to any one of claims 1 to 23, wherein the antibiotic is a polypeptide antibiotic, in particular colistin or colistin B, or a pharmaceutically acceptable derivative of any one thereof.

27. The use, method or composition of any of claims 1-23, wherein the pathogenic bacteria is a gram positive bacteria.

28. The use, method or composition of any of claims 1-23, wherein the pathogenic bacteria is a gram negative bacteria.

29. The use, method or composition of any of claims 1-23, wherein the pathogenic bacteria is Klebsiella (Klebsiella spp), erythromycin-resistant group a Streptococcus (Streptococcus spp.), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (Enterococcus) (VRE), Escherichia coli (Escherichia coli) or Streptococcus pneumoniae (Streptococcus pneumoniae).

Background

The present invention relates to the use of zinc ionophores or combinations of zinc (II) salts and zinc ionophores as antibiotic adjuvants or enhancers. Their use in restoring the sensitivity of one or more drug resistant bacteria (resistant bacteria) to one or more antibiotics is also described. Also described are pharmaceutical compositions comprising an antibiotic in combination with a zinc ionophore, a zinc (II) coordination compound or a zinc (II) salt in combination with a zinc (II) ionophore, as well as methods of treating bacterial infections.

Summary of The Invention

The present invention is based, at least in part, on the surprising discovery that certain zinc ionophores or certain combinations of zinc (II) salts and zinc ionophores have the ability to restore the sensitivity of one or more antibiotic-resistant pathogenic bacteria to one or more antibiotics.

Thus, in one aspect, the present invention advantageously provides the use of a zinc ionophore in combination with a pharmaceutically acceptable zinc (II) salt or solvate thereof to restore the sensitivity of drug-resistant pathogenic bacteria to antibiotics. In certain embodiments, the zinc ionophore is pharmaceutically acceptable. In some embodiments, the zinc ionophore and zinc (II) salt are used in combination with an antibiotic. In certain embodiments, the antibiotic is not an aminoglycoside antibiotic.

In another aspect, the invention provides the use of a zinc ionophore in combination with a pharmaceutically acceptable zinc (II) salt or solvate thereof to inhibit resistance of a pathogenic bacterium to an antibiotic. Preferably, the antibiotic is not an aminoglycoside antibiotic. The invention also provides the use of a combination of a zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate thereof as an antibiotic adjuvant or antibiotic enhancer. In some embodiments, the antibiotic is not an aminoglycoside antibiotic. In some embodiments, the zinc ionophore and zinc (II) salt are used in combination with an antibiotic.

In another aspect, the invention also provides a method of restoring the sensitivity of drug-resistant pathogenic bacteria to antibiotics, the method comprising administering to a subject in need thereof an effective amount of a zinc ionophore in combination with an effective amount of a pharmaceutically acceptable zinc (II) salt. In some embodiments, the method further comprises administering an antibiotic.

In some embodiments, the zinc ionophore and zinc (II) salt are used in combination with an antibiotic. In some embodiments, the antibiotic is not an aminoglycoside antibiotic. In some embodiments, the zinc ionophore is pharmaceutically acceptable. In some embodiments, the zinc ionophore is in the form of a pharmaceutically acceptable derivative.

and a pharmaceutically acceptable carrier.

In some embodiments, the antibiotic is not an aminoglycoside antibiotic. In some embodiments, the pharmaceutical composition is used to restore the sensitivity of drug-resistant pathogenic bacteria to antibiotics. In some embodiments, the pharmaceutical formulation is used to suppress resistance of a pathogen to an antibiotic. In some embodiments, the pharmaceutical composition is for use in treating a bacterial infection.

The invention also provides the use of a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate or zinc (II) complex or pharmaceutically acceptable derivative thereof in the manufacture of a medicament for re-sensitizing drug-resistant pathogenic bacteria to an antibiotic or for suppressing the drug resistance of pathogenic bacteria to an antibiotic. Also provided is the use of a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate thereof or zinc (II) coordination compound or pharmaceutically acceptable derivative thereof in the manufacture of a medicament for separate, sequential or simultaneous use with an antibiotic or pharmaceutically acceptable derivative thereof in the treatment of a bacterial infection. Also provided is the use of a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate thereof or zinc (II) coordination compound or pharmaceutically acceptable derivative thereof in combination with an antibiotic or pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of a bacterial infection.

In another aspect, there is also provided a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate or zinc (II) complex or pharmaceutically acceptable derivative thereof for use in restoring the susceptibility of a drug-resistant pathogen to an antibiotic or for use in inhibiting the resistance of a pathogen to an antibiotic. Also provided are a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate or zinc (II) complex or pharmaceutically acceptable derivative thereof for use separately, sequentially or simultaneously with an antibiotic for the treatment of a bacterial infection. Also provided is a combination of a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate thereof or zinc (II) complex or pharmaceutically acceptable derivative thereof and an antibiotic or pharmaceutically acceptable derivative thereof for use in the treatment of a bacterial infection.

In another aspect, the present invention provides a pharmaceutical formulation comprising a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate thereof; and a pharmaceutically acceptable carrier; the medicinal preparation is used for restoring the sensitivity of drug-resistant pathogenic bacteria to antibiotics or inhibiting the drug resistance of pathogenic bacteria to antibiotics; wherein the antibiotic is not an aminoglycoside antibiotic.

It has now been found that, in at least one embodiment, the combination of the zinc (II) salts of the present invention with a zinc ionophore or zinc (II) coordination compound may restore the susceptibility of one or more species of a pathogen to one or more antibiotics or may inhibit the resistance of one or more pathogens to one or more antibiotics. Thus, certain combinations of zinc (II) salts, optionally in the form of zinc coordination compounds, and zinc ionophores may be used in combination with certain antibiotics to treat bacterial infections caused by one or more pathogenic bacteria that have previously developed resistance to the antibiotic. In some embodiments, the molar ratio of zinc (II) salt to zinc ionophore is about 1:2 or about 1: 1. In some embodiments, the combination of zinc (II) salt and zinc ionophore comprises an excess of zinc (II) salt, e.g., a stoichiometric excess of zinc (II) salt.

Without being bound by theory, it is believed that the zinc ionophore or ligand of the zinc (II) coordination compound can "mask" the charge on the zinc (II) cation to allow the zinc ion to diffuse more readily across the lipophilic bacterial cell membrane. After the zinc (II) ion/ionophore is transported into the bacterial cell, the combination is believed to exhibit antibacterial action by destabilizing the metal homeostasis (homeostatis). In some embodiments, in addition to transcriptional changes in heavy metal homeostatic genes, disruption of transcription by several essential virulence and metabolic systems by sub-inhibitory concentrations of zinc (II) ions/ionophores is observed. In some embodiments, these disruptions are believed to enhance the sensitivity of the antibiotic to the drug-resistant bacterial pathogen.

It has also been found that the zinc ionophore or ionophores of the invention have the ability to restore the sensitivity of antibiotic-resistant pathogenic bacterium or bacteria to antibiotic(s) or to inhibit resistance of pathogenic bacterium or bacteria to antibiotic(s) in the absence of zinc (II) salt.

Thus, in some embodiments, there are provided compositions, methods and uses of the present invention wherein the zinc ionophore is used in the absence of a zinc (II) salt. In some embodiments, the zinc ionophore is the only antibiotic adjuvant or antibiotic enhancer present. In some embodiments, the zinc ionophore is used in the absence of an additional zinc (II) salt. In some embodiments, the zinc (II) salt is used in the absence of another antibiotic adjuvant or antibiotic enhancer.

In some aspects, the invention also provides the use of a zinc ionophore to restore the sensitivity of drug-resistant pathogenic bacteria to antibiotics. In another aspect, there is provided the use of a zinc ionophore for the suppression of resistance of a pathogenic bacterium to an antibiotic. In some embodiments, the zinc ionophore is used in the absence of a zinc (II) salt or zinc (II) ion. The invention also provides the use of the zinc ionophore as an antibiotic adjuvant or antibiotic enhancer. In certain embodiments, the zinc ionophore is pharmaceutically acceptable. In some embodiments, the zinc ionophore is used in combination with an antibiotic. In some embodiments, the antibiotic is not an aminoglycoside antibiotic.

In another aspect, the invention also provides a method of restoring the sensitivity or suppressing the resistance of a drug-resistant pathogen to an antibiotic, the method comprising administering to a subject in need thereof an effective amount of a zinc ionophore. In some embodiments, the zinc ionophore is administered in the absence of an additional source of zinc (II) ions. In some embodiments, the method further comprises administering an antibiotic.

Inhibition or restoration of antibiotic resistance is used to treat bacterial infections in a subject, for example bacterial infections due to drug resistant bacteria. Thus, in at least one embodiment, the zinc ionophore of the present invention, when used in combination with an antibiotic to treat a bacterial infection; a combination of a zinc (II) salt or solvate thereof and a zinc ionophore; or zinc (II) coordination compounds are considered useful.

Thus, in another aspect, the invention also provides a method of treating a bacterial infection in a subject, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable zinc ionophore, or a combination of a pharmaceutically acceptable zinc ionophore and an effective amount of a pharmaceutically acceptable zinc (II) salt or solvate thereof, or a pharmaceutically acceptable zinc (II) coordination compound, simultaneously and/or sequentially with a therapeutically effective amount of an antibiotic or a pharmaceutically acceptable derivative thereof. In some embodiments, the antibiotic is not an aminoglycoside antibiotic.

Also provided are methods of treating a bacterial infection in a subject comprising administering a therapeutically effective and non-toxic amount of a pharmaceutical composition of the invention.

In another aspect, the invention provides a pharmaceutically acceptable zinc ionophore, or a combination of a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate thereof; or a pharmaceutically acceptable zinc (II) coordination compound, for use in the manufacture of a medicament for the treatment of a bacterial infection, wherein the medicament is for co-administration with an antibiotic or a pharmaceutically acceptable derivative thereof, simultaneously, sequentially or in any order, wherein the antibiotic is not an aminoglycoside antibiotic.

In another aspect, the invention provides a pharmaceutically acceptable zinc ionophore, or a combination of a pharmaceutically acceptable zinc ionophore and a pharmaceutically acceptable zinc (II) salt or solvate thereof; or a pharmaceutically acceptable zinc (II) coordination compound for use in the treatment of a bacterial infection, wherein the use is in combination with an antibiotic. In some embodiments, the use is for co-administration with the antibiotic or a pharmaceutically acceptable derivative thereof, simultaneously, sequentially or in any order. In some embodiments, the antibiotic is not an aminoglycoside antibiotic.

In another aspect, the invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable zinc ionophore, a pharmaceutically acceptable zinc (II) salt or solvate thereof and a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable zinc (II) coordination compound; an antibiotic or a pharmaceutically acceptable derivative thereof; and a pharmaceutically acceptable carrier. In some embodiments, the composition is used to treat a bacterial infection. In another aspect, the present invention provides a method of treating a bacterial infection in a subject, said method comprising administering a therapeutically effective and non-toxic amount of a pharmaceutical composition of the present invention.

Also provided are pharmaceutical compositions comprising a pharmaceutically acceptable zinc ionophore; a pharmaceutically acceptable zinc (II) salt or solvate thereof and a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable zinc (II) coordination compound, for use as an active therapeutic substance in the treatment of a bacterial infection in a subject. In some embodiments, the composition further comprises one or more therapeutically active substances. In some embodiments, the additional therapeutically active substance is an antibiotic or a pharmaceutically acceptable derivative thereof. In some embodiments, the additional therapeutically active substance is another antibiotic adjuvant or antibiotic enhancer.

In another aspect, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable zinc ionophore or a pharmaceutically acceptable derivative thereof, a zinc (II) salt or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable zinc ionophore or a pharmaceutically acceptable derivative thereof, or a zinc (II) coordination compound or a pharmaceutically acceptable derivative thereof; an antibiotic or a pharmaceutically acceptable derivative thereof; and a pharmaceutically acceptable excipient.

The invention also provides the use of a pharmaceutical composition of the invention in the treatment of a bacterial infection in a subject. Also provided are pharmaceutical compositions of the invention for treating a bacterial infection in a subject. The invention also provides the use of the pharmaceutical composition of the invention as an antibacterial agent. Pharmaceutical compositions of the invention for use as antibacterial agents are also provided.

The invention also provides the use of a pharmaceutically acceptable zinc ionophore, a pharmaceutically acceptable zinc (II) salt or solvate thereof and a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable zinc (II) coordination compound in the manufacture of a medicament for the treatment of a bacterial infection, wherein the medicament is for co-administration with an antibiotic, simultaneously, separately, sequentially or in any order.

The invention also provides a kit (kit) or a commercial package comprising: the following two pharmaceutical compositions are combined as active ingredients: a pharmaceutical composition comprising a pharmaceutically acceptable zinc ionophore, or a pharmaceutically acceptable zinc (II) salt or solvate thereof and a pharmaceutically acceptable zinc ionophore, or alternatively a pharmaceutically acceptable zinc (II) coordination compound or derivative thereof; and a pharmaceutical composition comprising an antibiotic or a pharmaceutically acceptable derivative thereof; and instructions for administering the combination simultaneously, separately or sequentially to a patient in need thereof for treating a bacterial infection.

In some embodiments, the zinc ionophore is an 8-hydroxyquinoline compound, such as the 8-hydroxyquinoline compound described in WO2004/007461, which is incorporated herein by reference in its entirety. In some embodiments, the zinc ionophore is a compound described in WO2007/147247, which is incorporated herein by reference in its entirety.

In some embodiments, the zinc ionophore is a compound of formula I:

wherein R is^1aAnd R^1bIndependently H, halogen, OR^2a、SR^2a、CF₃、C_1-4Alkyl or NR^2aR^2b；R^2aAnd R^2bIndependently is H or optionally substituted C_1-4An alkyl group;

or a pharmaceutically acceptable derivative thereof;

or a compound of formula II:

wherein:

R³and R⁵Independently is H; optionally substituted C_1-6An alkyl group; optionally substituted C_2-6An alkenyl group; optionally substituted C_2-6An alkynyl group; optionally substituted C_3-6A cycloalkyl group; optionally substituted aryl; an optionally substituted heterocyclic group; CN; OR (OR)⁶、SR⁶、COR⁶、CSR⁶、HCNOR⁶Or HCNN⁶Wherein R is⁶Is H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; NR (nitrogen to noise ratio)⁸R⁹Or SO₂NR⁸R⁹Wherein R is⁸And R⁹Independently selected from H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl and optionally substituted heterocyclyl; CONR⁹R¹⁰Wherein R is⁹As defined above, and R¹⁰Is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; CH (CH)₂CONR⁸R⁹Wherein R is⁸And R⁹As defined above; and (CH)₂)_nNR⁹R¹¹Wherein R is⁹As defined above, and R¹¹Selected from optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and SO₂R¹²Wherein R is¹²Is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, and n is 1-6;

R^4aand R^4bIndependently is H, optionally substituted C_1-4Alkyl or halogen;

or a pharmaceutically acceptable derivative thereof.

In some embodiments, the zinc ionophore is a compound of formula III:

wherein:

R³is H, optionally substituted C_1-6Alkyl, CONH₂Or (CH)₂)_nNR⁹R¹¹Wherein n is 0, 1,2 or 3;

R^4aand R^4bIndependently is H, optionally substituted C_1-4Alkyl or halogen;

R⁹is H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; and is

R¹¹Is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or SO₂R¹²Wherein R is¹²Is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl;

or a pharmaceutically acceptable derivative thereof.

In some embodiments, the zinc ionophore is 5-chloro-7-iodo-8-hydroxyquinoline [ clioquinol, CQ ]:

5, 7-dichloro-2- [ (dimethylamino) methyl ] -8-hydroxyquinoline [ PBT 2]:

or a pharmaceutically acceptable derivative of any one thereof.

In some embodiments, the zinc ionophore and zinc (II) salt are in the form of a zinc (II) coordination compound, preferably a pharmaceutically acceptable zinc (II) coordination compound or a pharmaceutically acceptable derivative thereof. In some embodiments, the zinc (II) coordination compound is a compound of formula VII:

Zn(II)[L]₂

VII

wherein each L is the same and is an anion of a zinc ionophore as defined herein;

or a pharmaceutically acceptable derivative thereof.

In some embodiments, the compound of formula VII is:

or a pharmaceutically acceptable derivative thereof.

In some embodiments, the antibiotic is a tetracycline, such as tetracycline, doxycycline or tigecycline (tigecycline); or a polypeptide antibiotic, such as a polymyxin, such as colistin (polymyxin E) or polymyxin B. In some embodiments, the antibiotic is a polypeptide antibiotic, such as colistin (polymyxin E) or polymyxin B.

In some embodiments, the zinc (II) salt is ZnCl₂、Zn(CH₃CO₂)₂Or ZnSO₄And the zinc ionophore is an 8-hydroxyquinoline compound as defined herein, e.g. clioquinol [ CQ]Or PBT 2. Alternatively, the zinc (II) salt and the zinc ionophore form a zinc (II) complex Zn (II) ([ L)]₂Wherein each L is the same and is an anion of an ionophore as defined herein. In certain embodiments, the antibiotic is a polypeptide antibiotic such as colistin (polymyxin E) or polymyxin B. In some embodiments, the pathogenic bacteria is Klebsiella (Klebsiella spp.), such as Klebsiella pneumoniae (Klebsiella pneumoniae); escherichia coli (Escherichia coli); erythromycin-resistant Group A Streptococcus (GAS); methicillin-resistant staphylococcus aureus (MRSA); or vancomycin-resistant enterococci (VRE).

In some embodiments of the methods, uses and compositions described herein, the zinc ionophore is used in the absence of a zinc (II) salt. In some embodiments, the zinc ionophore is an 8-hydroxyquinoline compound as defined herein, for example clioquinol [ CQ ] or PBT 2. In certain embodiments, the antibiotic is a polypeptide antibiotic, such as colistin (polymyxin E) or polymyxin B. In some embodiments, the pathogenic bacteria is klebsiella, such as klebsiella pneumoniae; or E.coli, for example MCR 1-positive E.coli.

Brief Description of Drawings

FIG. 1: PBT2 and zinc.

FIG. 1a illustrates the growth of GAS, MRSA and VRE on THY agar in the presence or absence of PBT2 (1.5. mu.M) and zinc (II) ions (400. mu.M).

FIG. 1b shows the presence or absence of PBT2(GAS is 1.5. mu.M, or MRSA and VRE are 6. mu.M) and ZnSO₄Time kill curves for GAS, MRSA, and VRE in THY broth (GAS 15 at 300. mu.M; MRSA and VRE at 600. mu.M). Error bars represent standard deviation from 2 biological replicate samples.

FIG. 1c is a graphical representation of the development of resistance during serial passages in the presence of sub-inhibitory concentrations of antimicrobial compounds in CAMHB. Data represent the average of 3 biological replicates.

Figure 1d shows CFU recovery from murine skin infection model 4 days after challenge with GAS or MRSA. Using ointment alone or with 5mM PBT2 and/or 50mM ZnSO per day₄(MRSA) or ZnCl₂(GAS) ointment to treat mice. Data are representative of two independent experiments, and values (═ P) were plotted for individual mice<0.05, unpaired t-test, nonparametric).

FIG. 2: PBT2 and zinc affect heavy metal homeostasis, metabolism and virulence.

FIG. 2a shows the results for GAS in CAMHB (4.75. mu.M PBT2+ 128. mu. MZnSO₄)、MRSA(2μM PBT2+50μM28ZnSO₄) And VRE (1.75. mu.M PBT2+ 128. mu.M ZnSO₄) Using PBT2 and ZnSO₄RNAseq transcriptome sequence analysis of treated bacteria. With log2 fold change>1/<1 and P<The 0.05 gene is shown above and below the dotted line, indicating the gene of interest. Data were collected from 3 biological replicate samples.

Figure 2b illustrates in a schematic way the transcript levels of selected genes determined by real-time PCR. Log (2) fold change was calculated relative to untreated controls and normalized to the reference gene using the Δ Δ Ct method (reference genes: GAS is proS, MRSA is rrsA, VRE is 23S). Error bars represent standard deviation of 3 biological replicate samples.

FIG. 2c illustrates the intracellular zinc (II) ion concentration of GAS and MRSA grown with or without PBT2 and zinc (II) ions as determined by ICP MS (GAS: 0.3. mu.M PBT2+ 50. mu.M ZnSO)₄)；MRSA：1μM PBT2+100μM ZnSO₄)。

FIG. 3: PBT2 and zinc reversed antibiotic resistance in a mouse wound infection model. The graph illustrates CFU recovery 4 days after wound infection with GAS. Mice were treated daily with ointment alone or with 2mM PBT2, 25mM ZnSO₄And/or 1.5% tetracycline ointment treatment 2 times. Values for each mouse are plotted. Data are representative of two independent experiments (═ P)<0.05，***＝P<0.001, unpaired t44 test, nonparametric).

FIG. 4: at time point of 0h 1.4x10 was used⁵CFU colistin-resistant klebsiella pneumoniae strain 52.145 Δ mgrB systemic (i.p.) infection model. Therapeutic dose: PBT21.67mg/kg; colistin 0.05 mg/kg. Arrows indicate treatment regimens.

FIG. 5: the development of resistance to klebsiella pneumoniae MS6671 during serial passages in the presence of sub-inhibitory concentrations of antibacterial compounds in cation-regulated Mueller Hinton broth. Data are representative of 3 biological replicates.

Description of The Preferred Embodiment

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. For the purposes of the present invention, the following terms are defined as follows.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The terms "individual", "patient" and "subject" are used interchangeably herein to refer to an individual of human or other animal origin, and include any individual for whom examination or treatment using the methods of the invention is desired. However, it should be understood that these terms do not imply the presence of symptoms. Suitable animals that fall within the scope of the present invention include, but are not limited to, humans, primates, livestock (e.g., sheep, cattle, horses, donkeys, pigs, poultry), laboratory test animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs), and captive wild animals (e.g., foxes, deer, wild dogs, birds, reptiles). In some embodiments, the individual is a human.

As used herein, the term "treatment" or the like refers to the administration of an agent to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or a symptom thereof, and/or therapeutic in terms of a partial and complete cure for a disease and/or a symptom thereof. The effect may be therapeutic in terms of a partial or complete cure for a disease or condition (e.g., a disease or condition mediated by a bacterial infection) and/or adverse effects due to the disease or condition. These terms also encompass any treatment of a disease or condition in a mammal, particularly a human, and include: (a) preventing the occurrence of symptoms of a disease or disorder or disease or condition in a subject who may be predisposed to the disease or disorder, but has not yet been diagnosed as having the disease or disorder (e.g., including diseases or disorders that may be associated with or caused by the primary disease or disorder, (b) inhibiting the disease or disorder, i.e., arresting its development, (c) alleviating the disease or disorder, i.e., causing regression of the disease or disorder, (d) alleviating symptoms of the disease or disorder and/or (e) reducing the frequency of occurrence of symptoms of the disease or disorder.

As used herein, the term "pharmaceutically acceptable derivative" includes pharmaceutically acceptable salts or solvates. The term may also include in vivo hydrolysable esters.

Pharmaceutically acceptable Salts are described, for example, in the Handbook of Pharmaceutical Salts, Properties, Selection, and Use; edited by P.Heinrich Stahl and Camile G.Wermuth.VHCA, Verlag Helvetica Chimica Acta, Z rich, Switzerland, and Wiley-VCH, Weinheim, Germany.2002. Their preparation is well known in the art.

Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Examples of organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. For example, the amine group of the compounds of the present invention may be reacted with an acid, such as hydrochloric acid, to form an acid addition salt, such as the hydrochloride or dihydrochloride.

Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Corresponding counterions derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium and magnesium salts. Organic bases include primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, and cyclic amines, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, and N-ethylpiperidine. For example, when a compound of the invention has a carboxylic acid group or a phenolic group, the compound can be reacted with a base to form a base addition salt.

The term "solvate" is a complex of variable stoichiometry formed by a solute (in the present invention, a zinc (II) salt, a zinc ionophore, or a zinc (II) complex) and a solvent. Such solvents should preferably not interfere with the biological activity of the solute. As an example, the solvent may be water, acetone, ethanol or acetic acid. Solvation methods are generally known in the art. In some embodiments, the solvate is pharmaceutically acceptable. In some embodiments, the solvate is a hydrate, e.g., a mono-, di-, or tri-hydrate.

As used herein, the term "pharmaceutically acceptable zinc (II) salt" refers to Zn²⁺A salt. Examples of pharmaceutically acceptable zinc (II) salts include zinc chloride, zinc acetate and zinc sulfate. Other pharmaceutically acceptable zinc (II) salt anions include bromide, phosphate, tosylate, mesylate, tartrate, citrate, succinate, malate and maleate. The zinc (II) salt may be in the form of a pharmaceutically acceptable solvate, e.g. a hydrate, e.g. a mono-, di-or tri-hydrate. In some embodiments, the combination of zinc (II) salt and zinc ionophore comprises a stoichiometric excess of zinc (II) salt.

When referred to herein, the term "pharmaceutically acceptable derivative" when used in reference to a zinc (II) coordination compound or zinc ionophore described herein includes, but is not limited to, pharmaceutically acceptable solvates, such as hydrates, e.g., mono-, di-and tri-hydrates; and salts, e.g., pharmaceutically acceptable cationic, anionic or acid addition salts. Salt derivatives may also form solvates, such as hydrates.

When referred to herein, the term "pharmaceutically acceptable carrier, excipient or diluent" is a solid or liquid filler, diluent or encapsulating substance that may be safely employed for systemic administration. Suitable pharmaceutically acceptable carriers, excipients and diluents are well known in the art.

The term "adjuvant" when referred to herein refers to a pharmacologically active agent that alters or improves the efficacy of another pharmacologically active agent. In addition to the primary pharmacologically active agent, an adjuvant is also delivered to enhance its efficacy. The term "antibiotic adjuvant" refers to an agent that alters or improves the efficacy of an antibiotic. As used herein, the term "potentiating agent" refers to an agent that enhances or increases the action of an antibiotic.

As used herein, the term "antibiotic" or the like refers to a chemical substance used in medicine that is capable of destroying or impairing or inhibiting or reducing the growth of certain microorganisms that cause infections or infectious diseases, particularly pathogenic bacteria. Antibiotics may be active against one or more types of bacteria, for example, one or both of gram-positive and gram-negative pathogenic bacteria, and are used to treat a wide range of bacterial infections.

In some embodiments, the antibiotics of the present invention include, but are not limited to, those approved for sale or management and pharmaceutically acceptable salts, solvates, or in vivo hydrolysable esters thereof.

Antibiotics are generally classified according to their mode of action and/or chemical class and/or the type of infection they treat. Classes and examples of antibiotics for the treatment of bacterial infections include:

aminoglycosides

Such as kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin B, C, E, and streptomycin.

Carbapenems

Such as ertapenem, doripenem, imipenem, meropenem

Cephalosporins (first generation)

For example cefadroxil, cefazolin, cephalothin, cephalexin

Cephalosporins (second generation)

For example cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime

Cephalosporins (third generation)

Such as cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil (ceftaroline fosamil)

Cephalosporins (fourth generation)

For example cefepime

Cephalosporins (fifth generation)

For example ceftaroline fosamil, ceftobiprole (ceftobiprole)

Glycopeptides

Such as teicoplanin, vancomycin, telavancin, dabofacin, otafancin

Lincosamides (Lincosamides)

Such as clindamycin, lincomycin

Lipopeptides

Such as daptomycin

Macrolides

Such as azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin (telithromycin), spiramycin

Monocyclic lactams (Monobactams)

Such as aztreonam

Nitrofurans

Such as furazolidone, nitrofurantoin

Oxazolidinones

Such as linezolid, pasirezolid, radzolid, tedizolid

Penicillins

Such as amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, ticarcillin

Polypeptides

Such as bacitracin, colistin (polymyxin E), polymyxin B

Quinolones/fluoroquinolones

Such as ciprofloxacin, enoxacin (enofloxacin), gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin

Sulfonamides

Such as mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfasalazine, sulfisoxazole

Tetracyclines

Such as for example, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, tigecycline

Additional antibiotics

Such as chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, thiamphenicol, tigecycline, tinidazole, trimethoprim, rifampin, rifapentine, pyrazinamide, isoniazid, ethionamide, ethambutol, cycloserine, dapsone, clofazimine.

These antibiotics are named according to their international non-patent name (INN). It is to be understood that each of the antibiotics described above will also have IUPAC chemical names, depending on their chemical structure, and may also have one or more patent or trademark names. The antibiotic may be in the form of a pharmaceutically acceptable derivative such as a salt, solvate or in vivo hydrolysable ester.

When referred to herein, the term "pharmaceutically acceptable derivative" when used in connection with the antibiotics described herein includes, but is not limited to, pharmaceutically acceptable salts, such as cationic salts, for example sodium or potassium; anionic salts such as chloride, acetate, sulfate, methanesulfonate, bromide, and the like; acid addition salts, such as hydrochloride; pharmaceutically acceptable solvates, such as hydrates; and esters, such as in vivo hydrolysable esters. The in vivo hydrolysable ester is an ester that hydrolyses upon administration to a subject to give a free carboxylate group, for example pivaloyloxymethyl ester. Suitable pharmaceutically acceptable derivatives of antibiotics are well known in the art.

Preferably, the antibiotic of the present invention is not an aminoglycoside antibiotic, and the antibiotic of the present invention may be referred to herein as a "non-aminoglycoside" antibiotic. In some embodiments, the antibiotic is not kanamycin a, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin B, C, E, and streptomycin. In some embodiments, the antibiotic is not amikacin. In some embodiments, the antibiotic is not a tetracycline antibiotic.

In some embodiments, the antibiotic is a polypeptide antibiotic, such as bacitracin; or polymyxins, e.g., colistin (polymyxin E) or polymyxin B. It is to be understood that the scope of the present invention includes additional polypeptide antibiotics, including additional polymyxin antibiotics. Polymyxin antibiotics are cationic polypeptide antibiotics well known in the art. They are mainly used for gram-negative bacterial infections. The invention includes pharmaceutically acceptable derivatives, such as salts and/or solvates, for example, anionic addition salts, sulfate derivatives or mesylate derivatives, of polymyxin antibiotics. In some embodiments, the colistin derivative is an anionic derivative in the form of colistin mesylate, for example in the form of colistin mesylate sodium salt (colistin methane sodium sulfonate [ CMS ]). In some embodiments, colistin is a cationic derivative of the colistin sulfate form. In some embodiments, the colistin or pharmaceutically acceptable derivative thereof is administered by oral, inhalation or topical route or by parenteral or intravenous route. In some embodiments, the polymyxin B derivative is polymyxin B sulfate. In some embodiments, polymyxin B and pharmaceutically acceptable derivatives thereof are administered by topical, intramuscular, intravenous, intrathecal, or ocular routes.

In some embodiments, the antibiotic is a tetracycline antibiotic or a pharmaceutically acceptable derivative thereof. Tetracycline antibiotics include tetracycline, oxytetracycline, doxycycline or minocycline, or tigecycline, such as tetracycline. Tetracyclines are broad spectrum antibiotics with activity against both gram-positive and gram-negative bacteria. In some embodiments, the tetracycline is administered orally or parenterally.

As used herein, unless otherwise described, the term "ionophore" refers to a chemical moiety, such as an organic compound, that reversibly binds ions, such as metal ions. Examples of ionophores include lipid soluble portions that transport ions, such as metal ions, across cell membranes. Preferably, the ionophore is pharmaceutically acceptable. In some embodiments, the ionophore may be in the form of a pharmaceutically acceptable derivative or prodrug.

As used herein, unless otherwise indicated, the term "zinc ionophore" or "zinc (II) ionophore" refers to an ionophore that reversibly binds zinc (II) ions. Preferably, the zinc ionophore is an organic compound. Organic compounds that act as zinc ionophores are well known in the art and are commercially available or can be synthesized according to known routes. It is understood that the zinc ionophore is capable of binding other metal ions. Examples of pharmaceutically acceptable zinc (II) ionophores include pyrithione [ 1-hydroxy-2 (1H) -pyrithione ] and substituted 1-hydroxy-2 (1H) -pyridinethiones. In another embodiment, pharmaceutically acceptable zinc (II) ionophores include 8-hydroxyquinolines as described in WO2004/007461 and US20080161353A1, such as clioquinol (5-chloro-7-iodo-quinolin-8-ol or 5-chloro-7-iodo-8-hydroxyquinoline) and PBT2(5, 7-dichloro-2- [ (dimethylamino) methyl ] quinolin-8-ol or 5, 7-dichloro-2- [ (dimethylamino) methyl ] -8-hydroxyquinoline). Additional zinc (II) ionophores include 8-hydroxyquinoline analogs and derivatives, such as compounds comprising two fused 6-membered rings bearing a nitrogen at least at the 1-position and a hydroxyl substituent at the 8-position on the 6-membered ring. It is understood that the zinc (II) ionophore may be in the form of a pharmaceutically acceptable derivative.

In some embodiments, the compositions, methods and uses of the present invention comprise the use of a zinc ionophore in the absence of zinc (II) ions or zinc (II) salts. It will be appreciated by those skilled in the art that zinc ions may naturally occur in biological systems, for example in humans, animals or bacteria. As used herein, reference to the absence of zinc (II) ions or zinc (II) salts is intended to mean the absence of any zinc (II) ions, optionally in the form of zinc (II), except those already present in biological systems.

Examples of zinc ionophores are disclosed and syntheses are described in the following documents, for example, WO2017/053696, WO2016/086261, WO 2014/163622; WO 2010/071944; WO 2007/147217; WO 2007/118276; WO 2005/095360; WO 2004/031161; and WO2004/007461, each of which is incorporated herein by reference in its entirety. The zinc ionophore may be in the form of a pharmaceutically acceptable derivative.

In some embodiments, the zinc ionophore is clioquinol or PBT 2. PBT2(5, 7-dichloro-2- [ (dimethylamino) methyl ] -8-hydroxyquinoline) has been subjected to a phase II clinical trial for the treatment of Alzheimer's disease and Huntington's disease. It has been found that PBT 212 is safe and well tolerated in humans up to 250 mg/day (oral) in humans, see, e.g., Lannfelt, l. et al Safety, efficacy, and biomarker definitions of PBT2 in targeting abeta a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, random, placebo-controlled trial. Lancet Neurol 7, 779-786, doi:10.1016/S1474-4422(08)70167-4 (2008); huntington Study Group Reach, H.D.I.safety, tolerability, and effectiveness of PBT2 in Huntington's disease: aphase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 14, 39-47, doi:10.1016/S1474-4422(14)70262-5 (2015); bush, A.I.the metal of Alzheimer 'S disease.J. Alzheimer' S Dis 33 supplement 1, S277-281, doi:10.3233/JAD 2012-129011 (2013). In some embodiments, the zinc ionophore is RA-HQ-12(5, 7-dibromo-2 [ (4-fluorophenylamino) methyl ] -8-hydroxyquinoline).

As used herein, the term "pathogenic bacteria" or "pathogenic bacteria" refers to bacteria that can cause an infection. In some embodiments, the bacteria are human pathogenic and cause a disease in a human. Bacteria can be classified as either gram-positive or gram-negative depending on the structure of the cell wall. Bacteria of the Genus Mycobacterium and related bacteria may be incorporated into the acid-fast bacteria. Members of the Genus Mycoplasma (Genus Mycoplasma) and related bacteria do not contain a cell wall and are considered to encompass another different class that also includes bacterial pathogens.

Gram-positive bacteria include bacilli (bacilli), such as actinomycetes (Actinomyces spp.); bacillus (Bacillus spp.); corynebacterium (Corynebacterium spp.), Clostridium (Clostridium spp.), Lactobacillus (Lactobacillus spp.); listeria (Listeria spp.); cocci (coccus), such as streptococci (Streptococcus spp.), including Streptococcus pyogenes (s. pyogenes), Streptococcus pneumoniae (s. pneumoconiae); enterococcus (Enterococcus spp.); streptomyces (Streptomyces spp.); and staphylococci (staphylococcus); including staphylococcus aureus (s. Examples of antibiotic-resistant bacteria include Group A Streptococcus (GAS), vancomycin-resistant enterococci (VRE), and methicillin-resistant staphylococcus aureus (MRSA).

Gram-negative bacteria include gram-negative bacilli, including, but not limited to, Acinetobacter baumannii (Acinetobacter baumannii), Acinetobacter iwoffii (Acinetobacter lwoffi), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Pseudomonas fluorescens (Pseudomonas fluorescens), Bordetella pertussis (Bordetella pertussis), Burkholderia spp (Burkholderia spp.), and Sphingobacterium sphingobacteriumsp (Sphingobacterium spp.); enterobacteriaceae (Enterobacteriaceae), including Citrobacter (Citrobacter spp.), Enterobacter (Enterobacter spp.), Escherichia coli, Klebsiella, Morganella (Morganella spp.), Proteus (Proteus spp.), Shigella (Shigella spp.), and Serratia marcescens (Serratia marcescens); and gram-negative cocci and cocci, including Brucella spp, Haemophilus spp and Neisseria spp.

In some embodiments, the bacteria comprise tetracycline-resistant and erythromycin-resistant GAS; multidrug resistant MRSA; multidrug resistance VRE; and colibacillosis and Klebsiella resistant strains.

Examples of bacterial strains include tetracycline-and erythromycin-resistant GAS strain HKU 16; multidrug resistance mrsasa 300; multidrug resistance VRE RBWH 1; klebsiella pneumoniae MS 6771; and MCR 1-positive E.coli strain MS 8345.

Method of the invention

In one aspect, the invention provides the use of a combination of a zinc (II) salt and a zinc ionophore to restore the sensitivity of at least one strain of drug-resistant pathogenic bacteria to an antibiotic; wherein the antibiotic is not an aminoglycoside antibiotic.

In some embodiments, the zinc ionophore is a compound of formula I:

wherein:

R^1aand R^1bIndependently H, halogen, OR^2a、SR^2a、CF₃Optionally substituted C_1-4Alkyl or NR^2aR^2b；

R^2aAnd R^2bIndependently is H or optionally substituted C_1-4An alkyl group;

or a pharmaceutically acceptable derivative thereof.

In some embodiments, R^1aAnd R^1bAre all H.

In some embodiments, R^2aAnd R^2bThe same is true. In some embodiments, R^2aAnd R^2bAre all C_1-4An alkyl group.

In some embodiments, the zinc ionophore includes a compound comprising two fused 6-membered rings, wherein at least the 1-position of the fused 6-membered ring contains a nitrogen and the 8-position contains a hydroxyl substituent.

In some embodiments, the zinc ionophore is a compound of formula II:

wherein:

R³and R⁵Independently is H; optionally substituted C_1-6An alkyl group; optionally substituted C_2-6An alkenyl group; optionally substituted C_2-6An alkynyl group; optionally substituted C_3-6A cycloalkyl group; optionally substituted aryl; an optionally substituted heterocyclic group; CN; OR (OR)⁶，SR⁶，COR⁶，CSR⁶，HCNOR⁶Or HCNN⁶Wherein R is⁶Is H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; NR (nitrogen to noise ratio)⁸R⁹Or SO₂NR⁸R⁹Wherein R is⁸And R⁹Independently selected from H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl and optionally substituted heterocyclyl; CONR⁹R¹⁰Wherein R is⁹As defined above, and R¹⁰Is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; CH (CH)₂CONR⁸R⁹Wherein R is⁸And R⁹As defined above; and (CH)₂)_nNR⁹R¹¹Wherein R is⁹As defined above, R¹¹Selected from optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and SO₂R¹²Wherein R is¹²Is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, and n is 1-6;

R^4aand R^4bIndependently is H, optionally substituted C_1-4Alkyl or halogen;

or a pharmaceutically acceptable derivative thereof.

In some embodiments, R³And R⁵Independently is H, optionally substituted C_1-6Alkyl, CONH₂Or (CH)₂)_nNR⁹R¹¹Wherein n is 0, 1,2 or 3;

R^4aand R^4bIndependently H, C_1-4Alkyl or halogen;

R⁹is H or optionally substituted C_1-4An alkyl group; and is

R¹¹Is optionally substituted C_1-4An alkyl group.

In some embodiments, R³And R⁵Independently is H, optionally substituted C_1-6Alkyl, CONH₂Or (CH)₂)_nNR⁹R¹¹Wherein n is 0, 1,2 or 3;

R^4aand R^4bIndependently H, C_1-4Alkyl or halogen;

R⁹is H or optionally substituted C_1-4An alkyl group; and is

R¹¹Is optionally substituted C_1-4An alkyl group.

In some embodiments, R³And R⁵Independently is H or (CH)₂)_nNR⁹R¹¹Wherein n is 0, 1 or 2, preferably 0 or 1. In some embodiments, C_1-4The alkyl group is unsubstituted.

In some embodiments, R^4aAnd R^4bIndependently H, C_1-4Alkyl, Cl or I.

In some embodiments, R^4aAnd R^4bIndependently H, Br, Cl or I. In some embodiments, R^4aAnd R^4bIndependently H, Cl or I.

In some embodiments, the compound of formula II is a compound of formula III:

wherein:

R³is H, optionally substituted C_1-6Alkyl, CONH₂Or (CH)₂)_nNR⁹R¹¹Wherein n is 0, 1,2 or 3;

R^4aand R^4bIndependently is H, optionally substituted C_1-4Alkyl or halogen;

or a pharmaceutically acceptable derivative thereof.

In some embodiments, R³Is CH₂N(C_1-4Alkyl radical)₂. In some embodiments, R³Is CH₂N(CH₃)₂. In some embodiments, R³The substituent is located at the 2-position of the ring. In some embodiments, R³Is H. In some embodiments, R³Is CH₂NH(4-F-C₆H₄)。

In some embodiments, R^4aAnd R^4bIndependently selected from H and halogen. In some embodiments, R^4aAnd R^4bIndependently H, Cl, Br or I. In some embodiments, R^4aAnd R^4bIndependently H, Cl or I; and R is³Is H or CH₂N(CH₃)₂. In some embodiments, R^4aAnd R^4bAre all Br.

For compounds of formula II or III, the variable R³Or R⁵By optional substituents is meant one or more groups selected from: c_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, aryl, heterocyclyl, halogen, halogeno C_1-6Alkyl, halo C_3-6Cycloalkyl, halo C_2-6Alkenyl, halo C_2-6Alkynyl, haloaryl, haloheterocyclyl, hydroxy, C_1-6Alkoxy radical, C_2-6Alkenyloxy radical, C_2-6Alkynyloxy, aryloxy, heterocyclyloxy, carboxy, haloAlkoxy, halo C_2-6Alkenyloxy, halogeno C_2-6Alkynyloxy, haloaryloxy, nitro C_1-6Alkyl, nitro C_2-6Alkenyl, nitroaryl, nitroheterocyclyl, azido, amino, C_1-6Alkylamino radical, C_2-6Alkenylamino group, C_2-6Alkynylamino, arylamino, heterocyclylaminoacyl, C_1-6Alkyl acyl radical, C_2-6Alkenyl acyl, C_2-6Alkynylacyl, arylacyl, heterocyclylacyl, acylamino, acyloxy, aldehyde group, C_1-6Alkylsulfonyl, arylsulfonyl, C_1-6Alkylsulfonylamino, arylsulfonylamino, C_1-6Alkylsulfonyloxy, arylsulfonyloxy, C_1-6Alkylsulfinyl (sulphonyl), C_2.6Alkylsulfinyl, arylsulfinyl, alkoxycarbonyl (carboalkoxy), aryloxycarbonyl (carboaryloxy), mercapto, C_1-6Alkylthio, arylthio, acylthio, cyano and the like. In some embodiments, the optional substituent is C_1-4Alkyl, halo C_1-4Alkyl, hydroxy, halogen, C_1-4Alkoxy or C_1-4An alkyl acyl group.

In some embodiments, the zinc ionophore of formula II, formula III, or formula IV is:

5-chloro-7-iodo-8-hydroxyquinoline (clioquinol):

5, 7-dichloro-2- [ (dimethylamino) methyl ] -8-hydroxyquinoline (PBT2):

or a pharmaceutically acceptable derivative of any one thereof.

In some embodiments, the zinc ionophore is 5, 7-dichloro-2- [ (dimethylamino) methyl ] -8-hydroxyquinoline (PBT2) or a pharmaceutically acceptable derivative thereof, such as a hydrochloric acid addition salt.

In some examples, the zinc ionophore is 5, 7-dichloro-2- [ (4-fluorophenylamino) methyl ] -8-hydroxyquinoline (RA-HQ-12):

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the zinc ionophore is a compound of formula IV:

wherein R is³、R^4a、R^4b、R⁵As defined above for compounds of formula II or III;

each X is CH or N;

each Y is CH, CO, CS or N;

or a pharmaceutically acceptable derivative thereof.

In some embodiments, the zinc ionophore is a compound of formula V, wherein said compound of formula V is a compound of formula (I) as defined in WO2004/007461, which is herein incorporated by reference in its entirety:

wherein R is¹' is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclyl, antioxidant, or targeting moiety;

r is H; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted aryl; an optionally substituted heterocyclic group; optionally substituted alkoxy; an antioxidant; a targeting moiety; COR (continuous operating reference)^6'Or CSR^6'Wherein R is^6'Is H, optionally substituted alkyl, optionally substituted alkenyl, hydroxy, optionally substituted aryl, optionally substituted heterocyclyl, antioxidant, targeting moiety, OR^7'、SR^7'Or NR^7'R^8'Wherein R is^7'And R^8'Identical or different and selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted heterocyclyl; CN; (CH)₂)_nNR^9'R^10'、HCNOR^9'Or HCNN^9'R^10'Wherein R is^9'And R^10'Identical or different and selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted heterocyclyl, and n is 1-4; OR (OR)^11'、SR^11'Or NR^11'R^12'Wherein R is^11'And R^12'Identical or different and selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted heterocyclyl or together form an optionally substituted heterocyclyl; or SONR^13'R^14'Wherein R is^13'And R^14'Identical or different and selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted heterocyclyl; and is

R^3'、R^4'、R^5'R and R' are the same or different and are selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted acyl, hydroxy, optionally substituted amino, optionally substituted thio (thio), optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted sulfonylamino, halogen, SO₃H. Amino, CN, CF₃An optionally substituted aryl group, an optionally substituted heterocyclyl group, an antioxidant or a targeting moiety,

and salts, hydrates, solvates, derivatives, prodrugs, tautomers and/or isomers thereof.

In some embodiments, the zinc ionophore is a compound of formula VI, wherein the compound of formula VI is a compound of formula (I) as defined in WO2007/147217, which is incorporated herein by reference in its entirety:

wherein:

R^2”is H; optionally substituted C_1-6An alkyl group; optionally substituted C_2-6An alkenyl group; optionally substituted C_2-6An alkynyl group; optionally substituted C_3-6A cycloalkyl group; optionally substituted aryl; an optionally substituted heterocyclic group; CN; OR (OR)^6”，SR^6”，COR^6”，CSR^6”，HCNOR^6”Or HCNN^6”Wherein R is^6”Is H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; NR (nitrogen to noise ratio)^8”R^9”Or SO₂NR^8”R^9”Wherein R is^8”And R^9”Independently selected from H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl and optionally substituted heterocyclyl; CONR^9”R^10”Wherein R is^9”As defined above, and R^10”Is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; CH (CH)₂CONR^8”R^9”Wherein R is^8”And R^9”As defined above; and (CH)₂)_nNR^9”R^11”Wherein R is^9”As defined above, and R^11”Selected from optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and SO₂R^12”Wherein R is^12”Is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, and n is 1-6;

R^xindependently selected from H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-6Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl; optionally substituted C_1-6Alkoxy, optionally substituted acyl, hydroxy, optionally substituted amino, optionally substituted thio, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted sulfonylamino, halogen, SO₃H, amino, CN, CF₃And halogen;

x' is CH or N;

y' is CH, CO, CS or N; and is

q is 1,2 or 3,

and salts, hydrates, solvates, derivatives, prodrugs, tautomers and/or isomers thereof.

The term "optionally substituted" with respect to compounds of formulas V and VI refers to a group that may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, aldehyde, halogen, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxyl, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, acylamino, alkoxylalkyl, haloalkenyl, nitroalkynyl, nitroaryl, nitrobenzyl, Alkylsulfonyloxy, arylsulfinyloxy, heterocyclic group, heterocyclic oxy, heterocyclic amino, halogenated heterocyclic group, alkylsulfinyl, arylsulfinyl, alkoxycarbonyl, aryloxycarbonyl, mercapto, alkylthio, benzylthio, acylthio, cyano, phosphorus-containing group, and the like. Preferably, the optional substituent is C_1-6Alkyl, more preferably C_1-4An alkyl group; CF (compact flash)₃(ii) a Fluorine; chlorine; iodine; a cyano group; c_1-6Alkoxy, more preferably C_1-4An alkoxy group; an aryl group; a heteroaryl group; an amino group; or an alkylamino group.

As used herein, unless otherwise defined, the term "optionally substituted" typically refers to the substitution of a hydrogen atom on a group having a non-hydrogen moiety as described below. Any optionally substituted group may carry one, two, three or more optional substituents.

In some embodiments, the optional substituents are selected from: optionally substituted C_1-6An alkyl group; optionally substituted C_6-10An aryl group; halogen; -OH; -NH₂；-NO₂；-SO₂NH₂；-CO₂H；-CO₂(C_1-6Alkyl groups); -NHCO₂(C_1-6Alkyl groups); -NH-COR^aWherein R is^aIs H or C_1-6An alkyl group; -NR^aR^bWherein R is^aIs H or C_1-6Alkyl and R^bIs H or C_1-6An alkyl group; -C (O) NR^aR^bWherein R is^aIs H or C_1-6Alkyl and R^bIs H, C_1-6An alkyl group; -C (O) R^aWherein R is^aIs H or C_1-6An alkyl group; or-Y-Q, wherein:

y is selected from: -O-, -S-, -NH-, -N (C)_1-6Alkyl) -, -NHSO₂-、-SO₂NH-、-NHCONH-、-NHCON(C_1-6Alkyl) -, -S (O)_q- (wherein q is 0, 1 or 2), -C (O) NH-, -C (O) N (CH)₃) -, -NHC (O) -, -C (O) -, -NHC (NH) NH-or is absent, and

q is selected from: optionally substituted C_6-10An aryl group; optionally substituted 5-to 10-membered C_1-9A heteroaryl group; optionally substituted 3-to 10-membered C_1-9A heterocyclic group; optionally substituted C_3-10A cycloalkyl group; optionally substituted C_1-6An alkyl group; optionally substituted C_2-6An alkenyl group; optionally substituted C_2-6An alkynyl group; and hydrogen.

In some embodiments, optional substituents for alkyl groups are selected from: c_3-7Cycloalkyl, heterocyclyl, OR, SR, CF₃、CO₂R and halogen; wherein R is selected from H; c_1-6An alkyl group;optionally substituted C_6-10An aryl group; optionally substituted 5-to 10-membered C_1-9A heteroaryl group; optionally substituted 3-to 10-membered C_1-9A heterocyclic group; and optionally substituted C_3-10A cycloalkyl group.

In some embodiments, the optional substituents of the aryl group are selected from: c_1-6Alkyl radical, C_3-7Cycloalkyl, heterocyclyl, OR, SR, CF₃、CO₂R and halogen; wherein R is selected from H; c_1-6An alkyl group; optionally substituted C_6-10An aryl group; optionally substituted 5-to 10-membered C_1-9A heteroaryl group; optionally substituted 3-to 10-membered C_1-9A heterocyclic group; and optionally substituted C_3-10A cycloalkyl group.

The term "alkyl" includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like) and branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, and the like). Expression "C_x-yAlkyl "denotes an alkyl group (straight or branched) containing the indicated number of carbon atoms, wherein x is 1-2 and y is 2-6. For example, the term C_1-4Alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, sec-butyl and isobutyl.

In one embodiment, the straight or branched chain alkyl group has 6 or fewer carbon atoms (i.e., C)_1-6). In some embodiments, the straight or branched chain alkyl group has 4 or fewer carbon atoms (i.e., C)_1-4)。

The term "cycloalkyl" includes saturated cyclic aliphatic groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl). Term C_3-6Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. Likewise, preferred cycloalkyl groups have 3 to 7 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. As used herein, the term "heterocycloalkyl" refers to a cycloalkyl group that contains one or more endocyclic heteroatoms.

The term "aryl" refers to an aromatic monocyclic (e.g., phenyl) or polycyclic group, e.g., tricyclic, bicyclic, e.g., naphthalene, anthracenyl, phenanthrenyl. The aryl group may also be fused or bridged with an alicyclic or heterocyclic ring which is not aromatic so as to form a polycyclic ring. In some embodiments, aryl is phenyl.

As used herein, the term "heteroaryl" denotes a monocyclic or bicyclic ring, typically having up to 7 atoms in each ring, wherein at least one ring is aromatic and comprises 1-4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to: benzimidazole, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl (indoliyl), pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. As defined below for heterocycles, "heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. Where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that the attachment is via an aromatic ring or via a heteroatom-containing ring, respectively.

As used herein, the term "heterocycle" or "heterocyclyl" is intended to mean a 5-to 10-membered aromatic or non-aromatic heterocyclic ring containing 1-4 heteroatoms selected from O, N and S, and including bicyclic groups. Thus, "heterocyclyl" includes the heteroaryl groups recited above as well as dihydro and tetrahydro analogs thereof. Additional examples of "heterocyclyl" include, but are not limited to, the following: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolizinyl (indolizinyl), indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazolidinyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1, 4-dioxanyl, hexahydroazepinyl (hexahydroazepinyl), piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothienyl, and the N-oxides thereof. The heterocyclyl substituents may be attached through a carbon atom or a heteroatom. As used herein, "heterocycloalkyl" refers to a saturated heterocyclic group.

The term "ester" includes compounds and moieties that contain a carbon atom or heteroatom bonded to an oxygen atom that is bonded to a carbon of a carbonyl group. The term "ester" includes alkoxycarboxyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl and the like. Alkyl, alkenyl or alkynyl groups are as defined above. An in vivo hydrolysable ester is one which hydrolyses to provide a free carboxylate group upon administration to a subject. The prodrug may be in the form of an in vivo hydrolysable ester.

The term "halogen" includes fluorine, bromine, chlorine and iodine. The term "perhalogenated" generally refers to moieties in which all hydrogens are replaced with halogen atoms, e.g. CF₃。

The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur. In some embodiments, the heteroatoms are nitrogen and oxygen.

It is also understood that the definition of the variables specified for the general formulae described herein will result in molecular structures consistent with standard organic chemical definitions and valencies.

It should be noted that the structure of certain compounds of the present invention may include asymmetric centers, including asymmetric carbon atoms. It is therefore to be understood that isomers resulting from such asymmetry (e.g., all enantiomers, stereoisomers, rotamers, tautomers, diastereomers or racemates) are included within the scope of the present invention. Such isomers can be obtained in substantially pure form by classical separation techniques or by stereochemically controlled synthesis. In addition, the structures discussed in this application, as well as other compounds and moieties, also include all tautomers thereof. The compounds described herein can be obtained by art-recognized synthetic strategies. It should also be noted that the substituents of certain compounds of the present invention include isomeric cyclic structures. It is therefore to be understood that unless otherwise indicated, structural isomers of the particular substituents are included within the scope of the present invention.

In one aspect of the invention, a zinc (II) salt is combined with two molar equivalents of a zinc ionophore to form a zinc (II) complex compound of formula VII:

Zn(II)[L]₂

VII

wherein each L is the same and is the anion of a zinc ionophore of formula I, formula II, formula III, formula IV, formula V or formula VI as defined above.

The zinc (II) complex of the formula VII is referred to as formula VII according to the definition of L^I、VII^II、VII^III、VII^IV、VII^VOr VII^VI。

Thus, in the definition of formula VII^IIn some embodiments, L is a ligand of formula IA:

wherein R is^1aAnd R^1bAs defined above for the compounds of formula I.

Is defined as formula VII^IIIn some embodiments, L is a ligand of formula IIA:

wherein R is³、R^4a、R^4bAnd R⁵As defined above for the compound of formula II.

Is defined as formula VII^IIIIn some embodiments, L is a ligand of formula IIIA:

wherein R is³、R^4aAnd R^4bAs defined above.

Is defined as formula VII^IVIn some embodiments, L is a ligand of formula IVA:

wherein R is³、R^4a、R^4b、R⁵X and Y are as defined above for the compound of formula IV.

Is defined as formula VII^VOr of the formula VII^VIIn some embodiments, L is an anion of a compound of formula V or VI as defined above.

In some embodiments, L is [ PBT2] or [ CQ ]:

in some embodiments, L is [ RA-HQ-12]:

in some embodiments, the zinc (II) complex zn (II) ([ L ])]₂Is a complex having the formula:

wherein:

R³、R^4a、R^4band R⁵As defined above for compounds of formula II, III or V;

or a pharmaceutically acceptable derivative thereof.

In some embodiments, the lipophilicity [ LogP (octanol: water) ] of the zinc (II) complex of formula VII is less than 5.

It should be noted that certain zinc (II) complexes of the present invention may exist as geometric isomers, such as cis or trans isomers. The zinc (II) complexes of the invention may be in the form of one or other geometric isomers or a mixture of both. It is understood that geometric isomers are also included within the scope of the present invention.

In some embodiments, formula VII^IThe zinc (II) complex of (A) is:

it will be appreciated that the complex may also exist as a geometric isomer:

it is to be understood that both geometric isomers are encompassed by the present invention. The isomers may be present individually or as a mixture of two isomers in any ratio.

In some embodiments, the zinc (II) coordination compound of formula VII is zinc (II) [ PBT ]]₂：

Or a pharmaceutically acceptable derivative thereof, such as an acid addition salt, for example a hydrochloric acid addition salt.

The zinc (II) complexes mentioned in the following paragraphs also encompass combinations of zinc (II) salts with zinc ionophores, preferably in a molar ratio of about 1:2 or 1:1, or comprising a stoichiometric excess of zinc in a molar ratio of ionophore to zinc of from 1:4 to 1: 400.

One or more of the zinc (II) complexes of the invention or the combination of the zinc (II) salts of the invention with a zinc ionophore is believed to have activity as an inhibitor of antibiotic resistance in at least one pathogen and may restore the susceptibility of resistant pathogens to antibiotics. Thus, they are considered useful in the treatment of bacterial infections, for example in the treatment of one or more bacterial infections caused by antibiotic resistant bacteria. The zinc (II) complexes of the present invention are considered useful when administered to a subject in combination with an antibiotic.

Thus, the present invention also provides the use of a zinc (II) complex or zinc (II) salt of the invention in combination with a zinc ionophore as an antibiotic adjuvant or antibiotic enhancer. The zinc (II) complex of formula VII may be used as an antibiotic adjuvant or antibiotic enhancer in combination with an antibiotic for the treatment of bacterial infections.

Also provided is a method of treating a bacterial infection in a subject, the method comprising administering to a patient in need thereof an inhibitory amount of a zinc (II) complex or zinc (II) salt as defined above in combination with a zinc ionophore, simultaneously and/or sequentially with a therapeutically effective amount of an antibiotic or a pharmaceutically acceptable derivative thereof. In some embodiments, the bacterial infection is caused by an antibiotic-resistant bacterium.

In some embodiments, Zn²⁺the/Zn ionophore combination is Zn²⁺/PBT2, or the zinc (II) complex is zinc (II) [ PBT2]]₂And one or more of the following applies:

the antibiotic is a polypeptide antibiotic, such as polymyxin B or colistin, and the bacterial infection is by klebsiella, such as klebsiella pneumoniae; e.coli; erythromycin resistant Group A Streptococcus (GAS); methicillin-resistant staphylococcus aureus (MRSA); or vancomycin-resistant enterococcus (VRE);

the antibiotic is tetracycline and the bacterial infection is by klebsiella, e.g. klebsiella pneumoniae; erythromycin resistant Group A Streptococcus (GAS); streptococcus pneumoniae; or vancomycin-resistant enterococcus (VRE);

the antibiotic is tigecycline and the bacterial infection is caused by klebsiella;

the antibiotic is doxycycline and the bacterial infection is caused by klebsiella;

the antibiotic is oxacillin and the bacterial infection is caused by methicillin-resistant staphylococcus aureus (MRSA);

the antibiotic is erythromycin and the bacterial infection is caused by methicillin-resistant staphylococcus aureus (MRSA);

the antibiotic is ampicillin and the bacterial infection is caused by methicillin-resistant staphylococcus aureus (MRSA) or streptococcus pneumoniae;

the antibiotic is vancomycin and the bacterial infection is caused by vancomycin-resistant enterococcus (VRE);

the antibiotic is penicillin and the bacterial infection is caused by streptococcus pneumoniae;

the antibiotic is chloramphenicol and the bacterial infection is caused by streptococcus pneumoniae.

In some embodiments, Zn²⁺the/Zn ionophore combination is Zn²⁺/PBT2, or the zinc (II) complex is zinc (II) [ PBT2]]₂The antibiotic is a polypeptide antibiotic, such as polymyxin B or colistin, and the bacterial infection is caused by a colistin-resistant pathogen, such as Pseudomonas (Pseudomonas spp.), such as Pseudomonas aeruginosa; or Acinetobacter (Acinetobacter spp.), such as Acinetobacter baumannii.

In some embodiments, Zn²⁺the/Zn ionophore combination is Zn²⁺the/RA-HQ-12 or zinc (II) complex is zinc (II) [ RA-HQ-12]₂The antibiotic is a polypeptide antibiotic, such as polymyxin B or colistin, and the bacterial infection is by klebsiella, such as klebsiella pneumoniae; erythromycin resistant Group A Streptococcus (GAS); methicillin-resistant staphylococcus aureus (MRSA); or vancomycin-resistant enterococcus (VRE). In some embodiments, Zn²⁺the/Zn ionophore combination is Zn²⁺the/RA-HQ-12 or zinc (II) complex is zinc (II) [ RA-HQ-12]₂The antibiotic is tetracycline and the bacterial infection is caused by erythromycin resistant Group A Streptococcus (GAS).

In some embodiments, Zn²⁺the/Zn ionophore combination is Zn²⁺The chloroiodoquinol or zinc (II) complex is zinc (II) [ CQ]₂And one or more of the following applies:

the antibiotic is a polypeptide antibiotic, such as polymyxin B or colistin, and the bacterial infection is by klebsiella, such as klebsiella pneumoniae; coli, e.g., MCR-1 E.coli (E.coli); erythromycin-resistant Group A Streptococci (GAS), such as Streptococcus pyogenes (Streptococcus pyogenes); methicillin-resistant staphylococcus aureus (MRSA); or vancomycin-resistant enterococcus (VRE);

the antibiotic is tetracycline and the bacterial infection is by klebsiella, e.g. klebsiella pneumoniae; or vancomycin-resistant enterococcus (VRE);

the antibiotic is oxacillin and the bacterial infection is caused by methicillin-resistant staphylococcus aureus (MRSA);

the antibiotic is erythromycin and the bacterial infection is caused by methicillin-resistant staphylococcus aureus (MRSA);

the antibiotic is ampicillin and the bacterial infection is caused by methicillin-resistant staphylococcus aureus (MRSA);

the antibiotic is vancomycin and the bacterial infection is caused by vancomycin-resistant enterococci (VRE).

In some embodiments, Zn²⁺the/Zn ionophore combination is Zn²⁺/PBT2, or the zinc (II) complex is zinc (II) [ PBT2]]₂And one or more of the following applies:

the bacterial infection is caused by klebsiella, e.g. klebsiella pneumoniae, and the antibiotic is polymyxin B, colistin, tetracycline, tigecycline or doxycycline;

the bacterial infection is caused by MCR-1 E.coli and the antibiotic is polymyxin B or colistin;

the bacterial infection is caused by vancomycin-resistant enterococcus (VRE) and the antibiotic is colistin, polymyxin B, tetracycline or vancomycin;

the bacterial infection is caused by erythromycin-resistant Group A Streptococcus (GAS), such as streptococcus pyogenes, and the antibiotic is colistin, polymyxin B, or tetracycline;

the bacterial infection is caused by methicillin-resistant staphylococcus aureus (MRSA) and the antibiotic is colistin, polymyxin B, oxacillin, ampicillin or erythromycin;

the bacterial infection is caused by streptococcus pneumoniae and the antibiotic is tetracycline, penicillin, ampicillin or chloramphenicol.

In some embodiments, Zn²⁺the/Zn ionophore combination is Zn²⁺The chloroiodoquinol or zinc (II) complex is zinc (II) [ CQ]₂And one or more of the following applies:

the bacterial infection is caused by streptococcus pneumoniae and the antibiotic is tetracycline, penicillin, ampicillin or chloramphenicol;

the bacterial infection is caused by klebsiella pneumoniae and the antibiotic is tetracycline, polymyxin B or colistin;

the bacterial infection is caused by MCR-1 E.coli and the antibiotic is polymyxin B or colistin;

the bacterial infection is caused by erythromycin-resistant Group A Streptococcus (GAS), such as streptococcus pyogenes, and the antibiotic is colistin or polymyxin B;

the bacterial infection is caused by methicillin-resistant staphylococcus aureus (MRSA) and the antibiotic is colistin, polymyxin B, oxacillin, ampicillin or erythromycin.

In some embodiments, the bacterial infection is caused by tetracycline-resistant and erythromycin-resistant GAS; multidrug resistant MRSA; or VRE.

In some embodiments, the bacterial infection is caused by tetracycline-and erythromycin-resistant GAS strain HKU 16; multidrug resistance MRSA USA 300; or VRE RBWH 1.

In some embodiments, the bacterial infection is caused by drug resistant gram negative klebsiella pneumoniae MS6771 or MCR 1-positive escherichia coli strain MS 8345.

In some embodiments, the bacterial infection is caused by colistin-resistant gram-negative pathogens, such as Pseudomonas aeruginosa strain 253-43-C and Acinetobacter baumannii strain 42-A.

In some embodiments, the antibiotic is a polypeptide antibiotic such as colistin or polymyxin B or a pharmaceutically acceptable derivative of any one thereof, and Zn²⁺the/Zn ionophore combination is Zn²⁺/PBT 2. In some embodiments, the antibiotic is a polypeptide antibiotic such as colistin or colistin B, and the zinc (II) coordination compound is Zn (II) [ PBT2]₂Or a pharmaceutically acceptable derivative of any one thereof.

In some embodiments, the antibiotic is a polypeptide antibiotic such as colistin or polymyxin B or a pharmaceutically acceptable derivative of any one thereof, and Zn²⁺the/Zn ionophore combination is Zn²⁺/RA-HQ-12. In some embodiments, the antibiotic is a polypeptide antibiotic such as colistin or polymyxin B, and the zinc (II) coordination compound is Zn (II) [ RA-HQ-12]₂Or a pharmaceutically acceptable derivative of any one thereof.

In some embodiments, the antibiotic is a polypeptide antibiotic such as colistin or polymyxin B or a pharmaceutically acceptable derivative of any one thereof, and Zn²⁺the/Zn ionophore combination is Zn²⁺/clioquinol. In some embodiments, the antibiotic is a polypeptide antibiotic such as colistin or polymyxin B or a pharmaceutically acceptable derivative of any one thereof, and the zinc (II) coordination compound is zn (II) [ CQ]₂Or a pharmaceutically acceptable derivative thereof.

In the absence of a zinc (II) salt or zinc ion source, the zinc ion carrier or carriers of the invention are believed to have activity as inhibitors of antibiotic resistance in at least one pathogenic bacterium and may restore the susceptibility of the resistant pathogen to an antibiotic. Thus, it is believed that the zinc ionophores of formulae I-VI in combination with antibiotics can be used to treat bacterial infections, and preferably to treat one or more bacterial infections caused by antibiotic-resistant bacteria.

In another aspect, the invention also provides the use of a zinc ionophore for restoring the sensitivity of drug-resistant pathogenic bacteria, preferably drug-resistant gram-negative bacteria, to antibiotics. In another aspect, there is provided the use of a zinc ionophore for the suppression of resistance of a pathogenic bacterium to an antibiotic. The invention also provides the use of the zinc ionophore as an antibiotic adjuvant or antibiotic enhancer. In certain embodiments, the zinc ionophore is pharmaceutically acceptable. In some embodiments, the zinc ionophore is used in combination with an antibiotic to treat a bacterial infection. In some embodiments, the zinc ionophore is a compound of formula I, II, III, IV, V or VI as defined above. In some embodiments, the zinc ionophore is clioquinol or PBT 2. In some embodiments, the zinc ionophore is RA-HQ-12. The zinc ion carriers of the invention are considered useful when administered to a subject in combination with an antibiotic.

Also provided is a method of treating a bacterial infection in a subject, the method comprising administering to a patient in need thereof an inhibitory amount of a zinc ionophore as defined above, simultaneously and/or sequentially with a therapeutically effective amount of an antibiotic or a pharmaceutically acceptable derivative thereof. In some embodiments, the bacterial infection is caused by an antibiotic-resistant bacterium.

In some embodiments, the antibiotic is not an aminoglycoside antibiotic. In some embodiments, the antibiotic is a polypeptide antibiotic, such as polymyxin B or colistin; and the zinc ionophore has the formula I-VI, e.g., an ionophore of formula III, e.g., clioquinol or PBT 2. In some embodiments, the drug-resistant pathogenic bacteria are gram-negative bacteria, such as klebsiella or escherichia coli.

In some embodiments, the antibiotic is a polypeptide antibiotic, such as polymyxin B or colistin or a pharmaceutically acceptable derivative of any one thereof, and the adjuvant is a zinc ionophore of formulae I-VI, such as clioquinol or PBT2, and the bacterial infection is caused by klebsiella, such as klebsiella pneumoniae, including MS 6771; or E.coli, for example MCR 1-positive E.coli strain MS 8345.

In some embodiments, the antibiotic is a polypeptide antibiotic, such as polymyxin B or colistin or a pharmaceutically acceptable derivative of any of them, and the antibiotic adjuvant or antibiotic enhancer is:

zinc ionophores of the formulae I to VI, such as clioquinol or PBT2 or a pharmaceutically acceptable derivative thereof;

a combination of a zinc (II) salt or a pharmaceutically acceptable solvate thereof and a zinc ionophore of formulae I-VI, such as clioquinol or PBT2 or a pharmaceutically acceptable derivative thereof; or

Zinc (II) coordination compounds of the formula VII, e.g. Zn (II) [ CQ]₂Or Zn (II) [ PBT2]₂。

In some embodiments, the antibiotic is a polypeptide antibiotic, such as polymyxin B or colistin or a pharmaceutically acceptable derivative of any thereof, and the antibiotic adjuvant or antibiotic enhancer is RA-HQ-12 or a pharmaceutically acceptable derivative thereof; a combination of a zinc (II) salt or a pharmaceutically acceptable solvate thereof and RA-HQ-12 or a pharmaceutically acceptable derivative thereof; or Zn (II) [ RA-HQ-12]₂。

Compositions of the invention

The zinc ionophores of the present invention are commercially available or can be prepared by synthetic routes well known in the art.

1-hydroxypyridine-2-thione (PYT, Compound of formula I, R^1a＝R^1bH) commercially available from, for example, Aldrich-SigmaCo LLC. Substituted 1-hydroxypyridine-2-thiones of formula I can be prepared according to known methods. For example, 1-hydroxypyridine-2-thiones substituted in the 6-position with NH alkyl, O-alkyl or S-alkyl may be prepared according to the methods described in WO2000/067699 and US 5675013. The substituted alkyl or CF can be prepared from the corresponding 2-bromodihydropyridines by reaction with 3-chloroperoxybenzoic acid and then treatment with sodium hydrosulfide according to the routes described, for example, in J.Med.Chem.2014, 57, 16, 7126-Asonic acid 7135 and in J.Amer.Chem.Soc, 1950, 72(10), 4362-Asonic acid 4364₃Substituted 1-hydroxypyridine-2-thione compounds. 1-substituted OH, SH, O-alkyl or S-alkyl in the 4-and/or 5-ring position by OH, SH, O-alkyl or S-alkyl is described in JP47040057, JP47040052 and Polish Journal of Chemistry, 2007, 81, 1869-synthesis of hydroxypyridine-2-thione compounds.

Clioquinol (5-chloro-7-iodo-8-quinolinol, CQ) is readily available from commercial sources, such as Sigma-aldrich co LLC.

The 8-hydroxyquinoline ionophores of formulae II, III and V are commercially available from, for example, Sigma-Aldrich Co LLC or can be synthesized according to known methods or as described herein. Certain zinc ionophores are commercially available or can be prepared according to methods such as j.med chem., 1972, 987-^4aAnd R^4bIs H, alkyl or halogen. Synthesis of 8-hydroxyquinoline ionophores from commercially available aniline derivatives by the Skraup reaction is described in Organic Synthesis, Coll. Vol.1, 478(1941), where R is^4aAnd R^4bIs H or alkyl. WO2014/66506a2 describes the synthesis of 5-bromo-7-alkyl-8-hydroxyquinoline ionophores from the corresponding 7-alkyl-8-hydroxyquinoline compounds using N-bromosuccinimide in tetrahydrofuran. The 8-hydroxyquinoline ionophore is commercially available, wherein R^4aAnd R^4bAre all H, and R³And/or R⁵The substituent being in the 2-position of the ring and being NH₂、CH₃、CO₂H or CONH₂. May be prepared according to the methods described in e.g.WO 2017/053696, WO2016/086261, WO2010/071944, WO 2007/147217; WO 2007/118276; WO 2005/095360; preparation of 8-hydroxyquinoline ionophores by the routes described in WO2004/031161 and WO2004/007461 and US2014/296251, wherein R is³And/or R⁵The substituent being in the 2-position of the ring and being-CH₂NR⁹R¹¹。

Zinc ionophores of formula IV, V or VI may be prepared according to the methods described in, for example, WO2007/147217 and WO 2004/007461.

PBT2 was synthesized using the synthetic pathway described in US20080161353a1(Prana Biotechnology Limited).

RA-HQ-12 was synthesized using the synthesis pathway described in WO2017/053696(University of Florida Research Foundation incorporated).

The zinc (II) coordination compounds of formula I can be prepared by known routes from a zinc (II) salt and the desired ligand (ionophore) using conventional methods well known in the art; see, e.g., Magda d. et al Cancer res.2008jul 1; 68(13): 5318-5325.doi 10.1158/0008-5472.CAN-08-0601, PMCID: PMC3033660, NIHMSID: NIHMS243995, Synthesis and Anticancer Properties of Water-solvent Zincionophores.

In general, the zinc (II) complexes of the invention can be prepared by reacting a zinc (II) salt, such as zinc (II) chloride, zinc (II) acetate or zinc (II) sulfate, with an appropriate amount of the desired zinc ionophore (ligand), usually in stoichiometric excess, in a suitable solvent, such as alcohol, water, acetone, N-dimethylformamide or dimethyl sulfoxide. The zinc (II) complex can be isolated by known methods, for example by precipitation and then filtration. The resulting zn (ii) complex can be purified by conventional methods such as recrystallization or chromatography. Ligands can be obtained, for example, from Sigma Aldrich Co LLC, or can be prepared according to known methods.

Formula VII may be prepared by reacting zinc (II) chloride with 2.5 molar equivalents of the desired pyrithione^IWherein L is 1-hydroxypyridine-2-thione (also known as pyrithione or PYT):

and R is^1aAnd R^1bAs defined above for compounds of formula I or IA. For example, Zn [ PYT) may be prepared by reacting Zn (II) chloride with 2.5 molar equivalents of pyrithione in dimethylsulfoxide]₂As shown in scheme 1.

Scheme 1

Formula VII^II-VIBy reacting one equivalent of a zinc (II) salt, such as zinc (II) chloride or zinc (II) acetate, with two equivalents of the desired ionophore of the formula II, III, IV, V or VI in methanol or acetone according to methods well known in the art and, for example, the following general formula II, 8jul 1; 68(13): 5318-5325.doi 10.1158/0008-5472.CAN-08-0601, PMCID: PMC3033660, NIHMSID: n is a radical ofIHMS243995, Synthesis and cationic Properties of Water-solvent Zinc Ionophores, as shown in scheme 2.

Scheme 2

Certain zinc (II) complex compounds of the present invention are believed to be novel. Thus, in another aspect, the invention also provides a zinc (II) complex of formula VII.

The zinc ionophore or zinc (II) complex of the present invention may be in crystalline form. The crystalline zinc (II) complex or ionophore may exist as a polymorph. The zinc (II) complex or the ionophore may also be present in amorphous form. In some embodiments, the zinc (II) complex or ionophore may be in a solvate form (e.g., a hydrate), and these physical forms are contemplated to be within the scope of the present invention. The term "solvate" is a complex of variable stoichiometry formed by a solute (in the present invention, the zinc (II) complex or ionophore of the present invention) and a solvent. Such solvents should preferably not interfere with the biological activity of the solute. As an example, the solvent may be water, acetone, ethanol or acetic acid. Solvation methods are generally known in the art.

The zinc (II) complexes and zinc ionophores of the present invention may be in the form of salts, especially pharmaceutically acceptable acid addition salts. Clinically acceptable acid addition salts can be prepared from inorganic and organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Examples of organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

The invention also provides a pharmaceutical composition comprising an effective amount of a zinc (II) complex or a pharmaceutically acceptable derivative thereof, or an effective amount of a combination of a zinc ionophore or a pharmaceutically acceptable derivative thereof as defined above and a pharmaceutically acceptable zinc (II) salt, together with at least one pharmaceutically acceptable carrier or diluent.

Antibiotics are readily available from commercial sources, such as Sigma-Aldrich Co LLC, or may be synthesized by fermentative, semi-synthetic, or synthetic routes using known methods.

The antibiotics referred to herein may be in the form of pharmaceutically acceptable derivatives, such as pharmaceutically acceptable salts, e.g. sodium or potassium salts, chlorides, sulphates, methanesulphonates, and the like, or in vivo hydrolysable esters. The antibiotic may also be in the form of a solvate, such as a hydrate. The antibiotic is preferably in substantially pure form, preferably at least 98% pure, on a weight basis.

For example, pharmaceutically acceptable base addition salts of antibiotics can be prepared from inorganic or organic bases. Corresponding counterions derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium and magnesium salts. Organic bases include primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines) and cyclic amines, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, choline, betaine, ethylenediamine, glucosamine, N-alkylosamines, theobromine, purines, piperazine, piperidine and N-ethylpiperidine. The carboxylic acid groups can be reacted with bases to form base addition salts.

It is believed that the combination of the zinc (II) complex or zinc ionophore of the present invention and the pharmaceutically acceptable zinc (II) salt restores the sensitivity of the bacteria to antibiotics by altering the transition metal homeostasis within the bacterial cell.

Thus, the compositions, uses and methods of the present invention are believed to be useful for treating one or more bacterial infections caused by pathogenic gram positive or gram negative bacteria susceptible to antibiotics.

The compositions, uses and methods of the invention are believed to be effective against drug resistant bacteria. In some embodiments, the compositions, uses and methods may be used to treat a disease caused by klebsiella, e.g., klebsiella pneumoniae; e.coli; erythromycin resistant Group A Streptococcus (GAS); methicillin-resistant staphylococcus aureus (MRSA); or a bacterial infection caused by one or more of vancomycin-resistant enterococci (VRE).

The compositions, uses and methods of the invention are believed to be effective against diseases or conditions caused by bacterial infections, including, but not limited to, septicemia (septicemia), pneumonia, bronchiolitis, bronchitis, endocarditis, intraperitoneal infections, joint infections, meningitis, osteomyelitis, pelvic infections, peritonitis, pyelonephritis, and urinary tract infections, including cystitis and urethritis.

In the methods of treatment of the present invention, the zinc ionophore and zinc (II) salt may be administered together, simultaneously, sequentially or in any order. In some embodiments, the zinc ionophore and the zinc (II) salt are administered together by the same route. The combination of zinc ionophore and pharmaceutically acceptable zinc (II) salt or zinc (II) complex and antibiotic may be administered together, simultaneously, sequentially or in any order. The zinc ionophore and the zinc (II) salt or zinc (II) complex may be administered by the same or different routes as the antibiotic. The dosage regimen of the zinc ionophore and zinc (II) salt or zinc (II) complex and antibiotic may be the same or different and may each occur sequentially, sequentially or sporadically. In some embodiments, the components may be administered together as a co-formulation. In some embodiments, they may be administered simultaneously or sequentially in any order, by the same or different routes of administration.

Although the zinc ionophore and the zinc (II) salt or zinc (II) complex of the present invention can be administered in undiluted form for therapy, it is preferred to provide the zinc (II) complex of formula I as a pharmaceutical composition.

Thus, in another aspect of the invention, there is provided a pharmaceutical composition comprising a zinc ionophore of the invention and a zinc (II) salt or zinc (II) complex and at least one pharmaceutically acceptable carrier, excipient or diluent.

The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

According to the present invention, the zinc (II) complex or zinc (II) salt is administered under a therapeutic regimen that is non-toxic to the subject. The zinc (II) complex or zinc (II) salt/zinc ionophore combination may be administered in unit dosage form.

The pharmaceutical compositions of the invention or compositions for use in the methods of the invention may be formulated and administered using methods known in the art. Techniques for formulation and administration may be found, for example, in Remington: the Science and practice of Pharmacy, Loyd V.Allen, Jr (Ed), The Pharmaceutical Press, London, 22 nd edition, 9.2012.

The compositions of the present invention may be formulated for administration by any route. In some embodiments, the composition is formulated for oral administration. The oral preparation can be in the form of tablet, capsule, powder (powder), granule or liquid preparation. In some embodiments, the composition is formulated for topical administration. The topical formulation may be in the form of a cream, lotion, ointment or gel. In some embodiments, the composition is formulated for parenteral administration, for example by intramuscular, intrathecal, intraperitoneal, intravesical or intravenous routes.

The antibiotic is suitably administered in the form of a pharmaceutical composition together with at least one pharmaceutically acceptable carrier. In some embodiments, the antibiotic is suitable for parenteral administration, e.g., intravenous, intracapsular or intramuscular administration. Thus, suitable compositions for administration are injectable formulations, such as sterile parenteral solutions or suspensions. In some embodiments, the antibiotic may be administered orally.

Suitable unit doses and maximum daily doses of the antibiotic used in combination with the zinc (II) composition of the invention may be determined according to the unit dose and maximum daily dose normally used for a given antibiotic. Thus, the antibiotic may be administered to the patient in a daily dose of, for example, 250mg to 750mg Intravenous (IV) or orally once every 6 hours to 500mg to 1g IV or orally once every 6-8 hours, with a maximum dose of about 50 mg/Kg/day or 4 g/day.

The amount of zinc (II) salt and zinc ionophore administered will vary and can be determined according to the circumstances and the route of administration. In some embodiments, the molar ratio of zinc (II) salt to ionophore is about 1: 2. The amount of zinc (II) complex or zinc (II) salt and zinc ionophore and antibiotic administered will vary and can be determined according to the circumstances and the route of administration. The amount of zinc (II) complex or zinc salt/zinc ionophore administered should be non-toxic to the subject. In some embodiments, the amount of zinc administered is 2-100 mg/Kg/day per oral administration, for example: 2.5-50 mg/Kg/day; 2.5-30 mg/Kg/day; 2.5-25 mg/Kg/day or 2.5-10 mg/Kg/day. In some embodiments, the amount of zinc administered is no more than 50mg/Kg, such as 20mg/Kg per day or 10mg/Kg per day orally. It will be appreciated that the ratio of zinc (II) ion to zinc ionophore or zinc (II) complex to antibiotic administered will vary and can be determined according to the circumstances and route of administration. Furthermore, the proportions co-administered by the same route may be different from the proportions administered by the individual routes. In some embodiments, the molar ratio of antibiotic to zinc (II) ion is from 25:1 to 1: 10. In some embodiments, the molar ratio of antibiotic to zinc (II) ion (whether in combination with a zinc ionophore or as part of a zinc coordination compound) is from 10:1 to 1: 6; 5:1 to 1:5 or 10:1 to 1: 1. The ratio of zinc (II) salt to zinc ionophore applied may also vary. In some embodiments, the ratio of zinc (II) salt to zinc ionophore is from about 1:4 to 4:1, such as from 1:2 to 2:1 or about 1:2 or 1: 1. In some embodiments, the combination of zinc (II) salt and zinc ionophore comprises a stoichiometric excess of zinc (II) salt, e.g., a molar ratio of ionophore to zinc of from 1:4 to 1: 400.

As described above, the zinc (II) complex or a pharmaceutically acceptable derivative thereof or the zinc (II) salt and the zinc ionophore or a pharmaceutically acceptable derivative thereof may be the only active ingredients administered to the subject. However, in a preferred embodiment, the zinc (II) complex or zinc (II) salt/zinc ionophore combination is administered with other therapeutic agents. For example, the zinc composition can be administered in combination with one or more therapeutic agents. The combination may allow the compounds described above to be administered separately, sequentially or simultaneously with the other active ingredients. The combination may be provided in the form of a pharmaceutical composition. It is within the scope of the invention to administer with one or more other active ingredients.

In one aspect, the combination of the invention is suitably provided as a kit or commercial package comprising, as active ingredient, a pharmaceutical composition comprising a zinc (II) salt, a zinc ionophore, in combination with one or more additional pharmaceutical agents comprising a pharmaceutically active ingredient, e.g. an antibiotic; and instructions for administering the combination simultaneously, separately or sequentially to a patient in need thereof for use in treating a bacterial infection.

In another aspect, the combination of the invention is suitably provided as a kit or commercial package comprising, as active ingredient, a pharmaceutical composition comprising a zinc (II) complex in combination with one or more additional pharmaceutical agents comprising a pharmaceutically active ingredient, such as an antibiotic; and instructions for administering the combination simultaneously, separately or sequentially to a patient in need thereof for use in treating a bacterial infection.

In some embodiments, the combination of the invention is a unit dose or fixed dose combination, wherein the components of the combination are administered to the patient in the form of a single entity or dosage form.

In some embodiments, the zinc (II) complex or zinc (II) salt and zinc ionophore are administered with an antibiotic and optionally with one or more pharmaceutically active ingredients. In some embodiments, the antibiotic is colistin, polymyxin B, tetracycline, tigecycline (tigecycline), doxycycline, oxacillin, erythromycin, ampicillin, vancomycin, penicillin, or chloramphenicol. In some embodiments, the zinc (II) complex or zinc (II) salt and zinc ionophore and antibiotic are administered together with one or more additional active ingredients selected, for example, from the group consisting of: other bacterial resistance inhibitors, antibiotic enhancers, antibiotics or antibiotic adjuvants, including beta-lactamase inhibitors, such as clavulanic acid; or other antibiotic adjuvants, such as cilastatin, tazobactam and sulbactam. In some embodiments, the zinc (II) complex or zinc (II) salt and zinc ionophore combination is administered with one or more antibiotics, such as β -lactam antibiotics, e.g., carbapenems, penicillins, or cephalosporins; macrolides such as erythromycin, clarithromycin, or azithromycin; fluoroquinolones, such as ciprofloxacin or norfloxacin; sulfonamides, such as sulfamethoxazole or trimethoprim; tetracyclines, such as tetracycline or doxycycline.

As will be readily understood by those skilled in the art, the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the mammal to be treated. It is believed that the choice of the carrier or delivery system and the route of administration can be readily determined by one skilled in the art. In preparing any formulation containing the compound, care should be taken to ensure that the activity of the compound is not disrupted during the process and that the compound is able to reach its site of action without being disrupted. In some cases, it may be necessary to protect the compound by means known in the art, such as microencapsulation or coating (e.g., using an enteric coating). Similarly, the route of administration is selected such that the compound reaches its site of action.

The present invention also contemplates the use of the compositions of the present invention as a coating on surgical instruments, needles, cannulas, sutures, staples, catheters, stents, artificial joint replacements, and the like, as a prophylactic to reduce infectious bacterial infections during surgery, intravenous injection, catheterization, and the like. In some embodiments, there is provided the use of the composition of the present invention for coating a catheter.

Suitable formulations for the compounds of the invention can be readily determined by one skilled in the art using routine methods. The identification of preferred pH ranges and suitable excipients such as antioxidants is conventional in the art. Buffering systems are commonly used to provide a desired range of pH values and include carboxylic acid buffers such as acetates, citrates, lactates, and succinates. A variety of antioxidants can be used in such formulations, including phenolic compounds (e.g., BHT or vitamin E) and reducing agents (e.g., methionine or sulfite).

The compounds described above, or pharmaceutically acceptable salts thereof, may be prepared in parenteral dosage forms, including those suitable for intravenous, intrathecal and intracerebral or epidural delivery. Pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and should be preserved against reducing or oxidizing and contaminating action by microorganisms, such as bacteria or fungi.

The solvent or dispersion medium for the injectable solutions or dispersions can comprise any conventional solvent or carrier system for such compounds and may comprise, for example, water, ethanol, polyols (for example, glycerol, propylene glycol, and liquid polyethylene glycols, and the like), suitable mixtures, and vegetable oils. For example, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. If necessary, the action of microorganisms can be prevented by adding various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like). In many cases, it is preferred to include agents that regulate osmotic pressure, such as sugars or sodium chloride. Preferably, the formulation for injection will be isotonic with blood. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Pharmaceutical forms suitable for injectable use may be delivered by any suitable route, including intravenous, intramuscular, intracerebral, intrathecal, epidural, intravesicular administration or infusion. In some embodiments, the pharmaceutical form for injectable use may be administered by intravenous route or intravesicularly via a catheter.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients such as those enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-dried or freeze-dried sterile-filtered solutions of the active ingredient and any other desired ingredient.

Other pharmaceutical forms include oral and enteral formulations of the invention in which the active compound may be formulated with an inert diluent or with an edible carrier, or may be enclosed in hard or soft shell gelatin capsules or may be compressed into tablets or mixed directly with the food in the diet. For oral therapeutic administration, the active compounds may be incorporated into excipients and used in the form of ingestible tablets, buccal or sublingual tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage is obtained.

Tablets, troches, pills, capsules and the like may also comprise the following listed components: binders, such as gums, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch, potato starch alginic acid, and the like; lubricants, such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added; or a flavoring agent. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound together with sweetening, preservative, dye or flavouring agents.

Liquid preparations may also be administered enterally, either gastrically or esophagally.

Any ingredients used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used.

The invention also relates to any other form suitable for administration, such as topical administration, e.g. creams, lotions and gels; enteral preparations, such as suppositories; or a composition suitable for inhalation or intranasal delivery, such as a solution, dry powder, suspension or emulsion.

Pharmaceutically acceptable vehicles and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents in pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the composition.

It may be advantageous to formulate the composition in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units intended as unitary dosages for the individual mammals to be treated; each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle. The specification for the novel dosage unit forms of the present invention is determined by, and directly depends on: (a) the unique characteristics of the active substance and the specific therapeutic effect to be achieved, and (b) limitations inherent in the field of the use of mixed active substances for the treatment of diseases in living subjects suffering from a disease in which physical health is impaired.

As noted above, the primary active ingredient may be combined in a therapeutically effective amount with a suitable pharmaceutically acceptable carrier in dosage unit form for convenient and effective administration. For example, a unit dosage form may contain the principal active compound in an amount of from 0.25 μ g to about 200 mg. Expressed as a ratio, the active compound may be present in the carrier in an amount of from about 0.25 μ g to about 200 mg/mL. In the case of compositions containing supplementary active ingredients, the dosage is determined by reference to conventional dosages and modes of administration of the ingredients.

The terms "therapeutically effective amount" and "effective amount" refer to an amount sufficient to effect a treatment as defined below when administered to an animal, preferably a mammal, more preferably a human, in need of such treatment. The therapeutically effective amount or effective amount will vary depending on the subject and the nature of the symptom, disease or condition being treated, the severity of the symptom, disease or condition, and the mode of administration, and can be determined by one of ordinary skill in the art by routine means.

The invention will now be described with reference to some specific embodiments and the accompanying drawings. However, it is to be understood that the particularity of the following description does not supersede the generality of the invention as described in the foregoing.

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Zinc ionophore and use thereof

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