阅读说明：本技术 二十四元大环席夫碱在制备耐甲氧西林金黄色葡萄球菌感染药物中的应用 (Application of twenty-four-membered macrocyclic schiff base in preparation of methicillin-resistant staphylococcus aureus infection medicine ) 是由 苑立博 于 2020-07-02 设计创作，主要内容包括：本发明公开了二十四元大环席夫碱在制备耐甲氧西林金黄色葡萄球菌感染药物中的应用。本发明通过圆二色光谱、Western-Blot等方法发现二十四元大环席夫碱可以和耐甲氧西林金黄色葡萄球菌中<I>MecA</I>基因的核心序列形成G-四链体结构,从而抑制了相应青霉素结合蛋白PBP2a的表达。通过药敏实验证实二十四元大环席夫碱可以降低耐甲氧西林金黄色葡萄球菌对苯唑西林的最低抑菌浓度。所述二十四元大环席夫碱使用量为5μM时,最低可以使耐甲氧西林金黄色葡萄球菌的最低抑菌浓度降低为0.5μg/mL,达到使用β-内酰胺类药物治疗耐甲氧西林金黄色葡萄球菌感染的作用。(The invention discloses application of twenty-four-membered macrocyclic Schiff base in preparation of a methicillin-resistant Staphylococcus aureus infection drug. The invention discovers that the twenty-four-element macrocyclic Schiff base can be combined with methicillin-resistant staphylococcus aureus by methods such as circular dichroism spectrum, Western-Blot and the like MecA The core sequence of the gene forms a G-quadruplex structure, so that the expression of corresponding penicillin binding protein PBP2a is inhibited, and a drug sensitive experiment proves that the lowest bacteriostatic concentration of methicillin-resistant staphylococcus aureus to oxacillin can be reduced by the aid of the twenty-quaternary macrocyclic Schiff base, and when the usage amount of the twenty-quaternary macrocyclic Schiff base is 5 mu M, the lowest bacteriostatic concentration of methicillin-resistant staphylococcus aureus can be reduced to 0.5 mu G/mL, so that the effect of treating methicillin-resistant staphylococcus aureus infection by using β -lactam drugs is achieved.)

1. The application of the twenty-four-membered macrocyclic Schiff base in the preparation of the medicine for treating methicillin-resistant Staphylococcus aureus infection is characterized in that: the structural formula of the twenty-four-membered macrocyclic Schiff base is shown as a formula I:

2. the use of the twenty-four macrocyclic schiff base of claim 1 in the preparation of a medicament for the treatment of methicillin-resistant staphylococcus aureus infection, wherein: when the usage amount of the twenty-four-membered macrocyclic Schiff base is 5 mu M, the minimum inhibitory concentration of methicillin-resistant Staphylococcus aureus is reduced to 0.5 mu g/mL.

3. The use of the twenty-four macrocyclic schiff base of claim 1 in the preparation of a medicament for the treatment of methicillin-resistant staphylococcus aureus infection, wherein: the twenty-four-membered macrocyclic Schiff base and the beta-lactam antibiotics are used together to prepare the medicine for treating methicillin-resistant Staphylococcus aureus infection.

4. The use of a twenty-four membered macrocyclic schiff base according to claim 1 or 3, in the preparation of a medicament for the treatment of methicillin-resistant staphylococcus aureus infection, wherein: the medicine prepared from the twenty-four-membered macrocyclic Schiff base is in the types of injection, powder injection, oral preparation, buccal tablet, spray, capsule and suppository.

Technical Field

The invention relates to the technical field of medicines, in particular to application of twenty-four-membered macrocyclic Schiff base in preparation of a medicine for treating methicillin-resistant Staphylococcus aureus infection.

Background

In 1961, scientists first isolated methicillin-resistant staphylococcus aureus, a species that rapidly spread in the 90 s, which now led to infections throughout the world. The methicillin-resistant staphylococcus aureus is resistant to all other beta-lactam antibiotics with similar structures to methicillin except methicillin, and can also be resistant to aminoglycosides, macrolides, tetracyclines, fluoroquinolones, sulfonamides and rifampicin to different degrees by changing the action target of the antibiotics, generating modification enzymes, reducing membrane permeability and other different mechanisms, so that great challenge is brought to clinical treatment of infection caused by the methicillin-resistant staphylococcus aureus. At present, the drug resistance mechanism of methicillin-resistant staphylococcus aureus is generally considered to be mainly regulated by MecA gene, and the overexpression of the MecA gene leads to high expression of PBP2a protein. PBP2a is one of the family of penicillin binding proteins, but its active site has a very low affinity for β -lactam antibiotics. When normal penicillin binding proteins and β -lactam antibiotics are bound and inactivated, PBP2a can replace their functions and continue peptidoglycan synthesis, thereby maintaining the growth and reproduction of bacteria and thus exhibiting high drug resistance. How to reduce the expression quantity of PBP2a from the gene level and further reduce the drug resistance of methicillin-resistant staphylococcus aureus to beta-lactam antibiotics has very important significance.

Disclosure of Invention

The invention aims to solve the technical problem of providing the application of the twenty-four-membered macrocyclic schiff base in the preparation of the methicillin-resistant staphylococcus aureus infection medicament, wherein the structural formula of the twenty-four-membered macrocyclic schiff base is shown as a formula I:

further, the twenty-four-membered macrocyclic schiff base can reduce the expression level of the penicillin binding protein PBP2a in methicillin-resistant staphylococcus aureus to 11.7% of that of a control group.

Further, when the usage amount of the twenty-four-membered macrocyclic schiff base is 5 mu M, the minimum inhibitory concentration (oxacillin) of methicillin-resistant staphylococcus aureus can be reduced to 0.5 mu g/mL.

Furthermore, the medicine types prepared from the twenty-four-membered macrocyclic schiff base are injection, powder injection, oral preparation, buccal tablet, spray, capsule, suppository and the like.

Further, the twenty-four-membered macrocyclic Schiff base and the beta-lactam antibiotics are used together to prepare the drug for treating methicillin-resistant Staphylococcus aureus infection.

The twenty-four-membered macrocyclic Schiff base synthesized by the invention can inhibit the expression of MecA gene by enabling a key sequence of a MecA gene regulation and control region to form a G-quadruplex structure, so that the expression level of PBP2a is reduced, the minimum inhibitory concentration of beta-lactam drugs used by methicillin-resistant Staphylococcus aureus is greatly reduced, and the effect of treating methicillin-resistant Staphylococcus aureus infection by using conventional doses of beta-lactam drugs is achieved.

The invention has the advantages that:

1. the invention develops new medical application of the twenty-four-membered macrocyclic Schiff base, and can generate considerable economic benefit when being used as a medicament for treating methicillin-resistant Staphylococcus aureus infection.

2. The twenty-four-membered macrocyclic Schiff base used in the invention can be synthesized manually, has simple steps and high purity of synthesized products, and can ensure industrial production.

3. The twenty-four-membered macrocyclic Schiff base is stable in quality, and can be used as various dosage forms, such as: injection, powder for injection, oral preparation, buccal tablet, spray, capsule, suppository, etc.

Drawings

FIG. 1 is a nuclear magnetic resonance of a twenty-four member macrocyclic Schiff base¹And H, spectrum.

FIG. 2 is a nuclear magnetic resonance of a twenty-four member macrocyclic Schiff base¹³And C, spectrum.

FIG. 3 is a circular dichroism spectrum of MecA gene core sequence before and after action with twenty-four macrocyclic Schiff base.

FIG. 4 is the results of the minimum inhibitory concentrations (MIC values) before and after the action of methicillin-resistant Staphylococcus aureus and the twenty-four-membered macrocyclic Schiff base.

FIG. 5 is a Westerm-Blot result after incubation of penicillin binding protein PBP2a and a twenty-four membered macrocyclic Schiff base in methicillin-resistant Staphylococcus aureus.

Detailed Description

The present invention will be further described with reference to the following examples. It is to be understood that the following examples are illustrative only and are not intended to limit the scope of the invention, which is to be given numerous insubstantial modifications and adaptations by those skilled in the art based on the teachings set forth above.