阅读说明：本技术 异噻唑啉酮作为抗菌药物的增效剂的应用 (Application of isothiazolinone as synergist of antibacterial drug ) 是由 季辉 万荣峰 彭麟 于 2020-09-07 设计创作，主要内容包括：本发明公开了异噻唑啉酮作为抗菌药物的增效剂的应用,属于医药技术领域。经试验研究表明,当异噻唑啉酮与氨基糖苷类、多肽类、氟喹诺酮类等抗菌药物联用时,能够降低抗菌药物的用药剂量,不仅能在减少抗菌药物用量的情况下确保其对细菌的抗菌效果,同时对于临床分离的耐药性菌株具有明显的增效作用。(The invention discloses application of isothiazolinone as a synergist of an antibacterial drug, and belongs to the technical field of medicines. Experimental research shows that when isothiazolinone is used together with aminoglycosides, polypeptides, fluoroquinolones and other antibacterial drugs, the dosage of the antibacterial drugs can be reduced, the antibacterial effect of the isothiazolinone on bacteria can be ensured under the condition of reducing the dosage of the antibacterial drugs, and meanwhile, the isothiazolinone has an obvious synergistic effect on clinically separated drug-resistant strains.)

1. The use of isothiazolinones as potentiators of antibacterial agents.

2. Use according to claim 1, characterized in that: the isothiazolinone is selected from methylisothiazolinone, methylchloroisothiazolinone or benzisothiazolinone.

3. Use according to claim 1, characterized in that: the antibacterial agent is an antibacterial agent for resisting gram-negative bacteria.

4. Use according to claim 3, characterized in that: the antibacterial drug for resisting gram-negative bacteria is selected from aminoglycoside antibacterial drugs, polypeptide antibacterial drugs or fluoroquinolone antibacterial drugs.

5. Use according to claim 4, characterized in that: the antibacterial drug for resisting gram-negative bacteria is selected from colistin sulfate, enrofloxacin, neomycin sulfate, gentamicin sulfate or difloxacin.

6. An antibacterial pharmaceutical composition, characterized in that: the method comprises the following steps: isothiazolinone, antibacterial agent, and pharmaceutically acceptable carrier and/or excipient;

the weight ratio of the isothiazolinone to the antibacterial drug is 1: 2-4: 1.

7. The antibacterial pharmaceutical composition according to claim 6, wherein: the isothiazolinone is selected from methylisothiazolinone, methylchloroisothiazolinone or benzisothiazolinone.

8. The antibacterial pharmaceutical composition according to claim 6, wherein: the antibacterial agent is an antibacterial agent for resisting gram-negative bacteria.

9. The antibacterial pharmaceutical composition according to claim 8, characterized in that: the antibacterial drug is selected from aminoglycoside antibacterial drugs, polypeptide antibacterial drugs or fluoroquinolone antibacterial drugs.

10. The antibacterial pharmaceutical composition according to claim 9, characterized in that: the antibacterial drug for resisting gram-negative bacteria is selected from colistin sulfate, enrofloxacin, neomycin sulfate, gentamicin sulfate or difloxacin.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to application of isothiazolinone as a synergist of an antibacterial drug.

Background

Isothiazolinone is a novel high-efficiency broad-spectrum bactericide, has the advantages of high efficiency, low toxicity, environmental friendliness and the like, has gradually replaced a plurality of toxic and low-efficiency bactericides such as mercury since being developed and used in the field of bactericidal biocides, and is widely applied to the fields of agriculture, industry and the like (Leishchang et al, synthetic material aging and application, 47(7), 120-. It is widely used for mildew prevention and corrosion prevention in various fields of industrial production, and is also used as a main antibacterial preservative in some personal care products (daily cosmetics, washing products and the like). The sterilization mechanism of isothiazolinone is mainly electrophilic active bactericide, which relies on that the active part on the heterocyclic ring of isothiazolinone forms hydrogen bond with the base on DNA molecule in the protein in the bacterial body, and adsorbs on the cell of bacteria, thus playing the role of attacking the cell for nucleophilic, thus destroying the structure of DNA in the cell, leading it to lose relevant physiological, biochemical and metabolic activities, and leading the cell to die (shaking, pharmaceutical and chemical industry, 42(9), 103 (2016)).

Substances having an inhibiting and/or killing effect on bacteria and other microorganisms are collectively called antibacterial agents, and the antibacterial agents mainly include artificially synthesized antibacterial agents (quinolones and the like) and antibiotics. Antibiotics are metabolites of microorganisms (bacteria, fungi, and actinomycetes) that, at appropriate concentrations, kill or inhibit other pathogenic microorganisms. Antibacterial drugs play an important role in the prevention and control of diseases in humans and animals. However, when the microorganism is contacted with the antibacterial drug, the metabolic pathway is changed or corresponding inactivated substances are manufactured to resist the antibacterial drug, so that the drug effect of the antibacterial drug is reduced, and even the drug resistance is generated. At present, the similar medicines which can improve the drug effect of the antibacterial drugs and reduce the drug dosage, such as clavulanate potassium, sulbactam and the like, can compete beta-lactamase inhibitors, are combined with the beta-lactam antibacterial drugs, and generally can have obvious synergistic effect, thereby greatly improving the antibacterial activity; trimethoprim (TMP) is a bacterial dihydrofolate reductase inhibitor, and belongs to a synergist of sulfanilamide antibacterial drugs. Therefore, the research and development of the antibacterial synergist have important significance for improving the application of antibacterial drugs.

Disclosure of Invention

The invention aims to provide application of isothiazolinone as a synergist of antibacterial drugs.

In order to achieve the purpose, the invention adopts the following technical scheme:

the use of isothiazolinones as potentiators of antibacterial agents.

Further, the isothiazolinone is selected from methylisothiazolinone, methylchloroisothiazolinone or benzisothiazolinone.

Further, the antibacterial agent is an antibacterial agent against gram-negative bacteria.

Further, the antibacterial agent against gram-negative bacteria is selected from aminoglycoside antibacterial agents, polypeptide antibacterial agents or fluoroquinolone antibacterial agents.

Further preferably, the antibacterial drug against gram-negative bacteria is selected from colistin sulfate, enrofloxacin, neomycin sulfate, gentamicin sulfate or difloxacin.

An antibacterial pharmaceutical composition comprising: isothiazolinone, antibacterial agent, and pharmaceutically acceptable carrier and/or excipient;

the weight ratio of the isothiazolinone to the antibacterial drug is 1: 2-4: 1.

Further, the isothiazolinone is selected from methylisothiazolinone, methylchloroisothiazolinone or benzisothiazolinone.

Further, the antibacterial agent is an antibacterial agent against gram-negative bacteria.

Further, the antibacterial agent against gram-negative bacteria is selected from aminoglycoside antibacterial agents, polypeptide antibacterial agents or fluoroquinolone antibacterial agents.

Further preferably, the antibacterial drug against gram-negative bacteria is selected from colistin sulfate, enrofloxacin, neomycin sulfate, gentamicin sulfate or difloxacin.

Experimental research shows that when the isothiazolinone and the antibacterial drug are used together, the dosage of the antibacterial drug can be reduced, the antibacterial effect on bacteria can be ensured under the condition of reducing the dosage of the antibacterial drug, and meanwhile, the isothiazolinone and the antibacterial drug have an obvious synergistic effect on clinically separated drug-resistant strains. Therefore, isothiazolinone can be used as a synergist of antibacterial agents.

The invention provides a new application of isothiazolinone as an antibacterial drug synergist and also provides a new solution for prevention and control of drug-resistant bacteria. On one hand, the isothiazolinone serving as an antibacterial agent synergist can reduce the effective dosage of antibacterial agents such as aminoglycosides, polypeptides, fluoroquinolones and the like, thereby reducing the toxic and side effects of the medicaments to a certain extent and reducing the medicament cost. On the other hand, isothiazolinone can restore the effect of the antibacterial drug on drug-resistant bacteria, effectively treat bacterial infection, particularly drug-resistant bacteria infection, and has important clinical application value.

Detailed Description

The inventor unexpectedly discovers that isothiazolinone compounds have good synergistic effect on a series of antibacterial drugs, in particular aminoglycoside antibacterial drugs, polypeptide antibacterial drugs and fluoroquinolone antibacterial drugs through long-term and intensive research. On this basis, the inventors have completed the present invention.

The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.