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Application of methimazole serving in as and/or in preparation of metal beta-lactamase inhibitor

A technology of methimazole and lactamase, which is applied in the field of medicine, can solve problems such as methimazole that have not been reported yet, and achieve the effects of improving sensitivity, improving safety, and reversing drug resistance

Active Publication Date: 2021-08-06
GENERAL HOSPITAL OF SOUTHERN THEATRE COMMAND OF PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there is no effective metallo-β-lactamase inhibitor on the market
There is no report on methimazole as a metallo-β-lactamase inhibitor

Method used

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  • Application of methimazole serving in as and/or in preparation of metal beta-lactamase inhibitor
  • Application of methimazole serving in as and/or in preparation of metal beta-lactamase inhibitor
  • Application of methimazole serving in as and/or in preparation of metal beta-lactamase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1 Methimazole is to the determination of metallo-beta-lactamase inhibitory activity

[0047]After the substrate is hydrolyzed by the enzyme, the absorbance value will decrease. Therefore, the degree of substrate hydrolysis can be characterized by the change of absorbance, so as to judge the activity of the enzyme. Meropenem (50 μM) was used as the reporter substrate, and the absorbance change of the substrate after being hydrolyzed by metallo-β-lactamase was measured at a wavelength of 300 nm. The concentration of metallo-β-lactamase is 4nM, the buffer is 50mM HEPES (4-hydroxyethylpiperazineethanesulfonic acid), 0.1mM ZnSO 4 , pH=7.2, the reaction temperature is 25°C, and the specific experimental method is as follows:

[0048] 1. Determination of the inhibitory activity of methimazole on IMP-7 metallo-β-lactamases

[0049] (1) Dissolve methimazole in HEPES buffer and prepare different concentrations (0.1, 1, 10, 50, 100, 200, 300, 500 μM respectively), set...

Embodiment 2

[0063] Example 2 Evaluation of the combined use of methimazole and meropenem in inhibiting MBLs-producing resistant bacteria

[0064] The minimum inhibitory concentration (MIC) of methimazole combined with meropenem against MBLs resistant strains was determined by micro broth dilution method. The MBLs-producing strains used in the experiment were genetically engineered bacteria E.coli BL21(DE3) / pET28a-IMP-7, E.coli BL21(DE3) / pET28a-VIM-2 and E. .coli BL21(DE3) / pET28a-NDM-1.

[0065] FICI is used to judge the interaction when two drugs are used in combination, and is defined according to the following equation: FICI=FIC A +FIC B =C A / MIC A +C B / MIC B , where MIC A and MIC B are the MIC values ​​of compounds A and B used alone, and C A and C B is the drug concentration of compounds A and B in the effective combination. If FICI ≤ 0.5, it is considered that the two drugs have synergistic effect, 0.5 < FICI ≤ 4 indicates that the synergistic effect of the two drugs is ...

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Abstract

The invention belongs to the field of medicines, and discloses application of methimazole in serving as and / or preparation of a metal beta-lactamase inhibitor. The invention discloses the application of the methimazole and / or the derivative thereof in serving as and / or preparation of the metal beta-lactamase inhibitor for the first time, the methimazole and / or the derivative thereof has a good inhibition effect on metal beta-lactamase, can protect antibiotics from being degraded by bacteria, improves the sensitivity of the bacteria to the antibiotics, and reversing drug resistance of the bacteria to the antibiotics; and meanwhile, the methimazole and / or the derivative thereof have a good synergistic effect when being combined with the antibiotics, and can be used as an adjuvant drug for inhibiting the bacteria. The methimazole has small toxic and side effects on human bodies under normal clinical use dosage, and has good safety in many years when being clinically used as a medicine for treating hyperthyroidism.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the application of methimazole as and / or in the preparation of metallo-beta-lactamase inhibitors. Background technique [0002] β-lactam antibiotics have become the most commonly used antibiotics clinically due to their high efficiency and low toxicity, and play a very important role in the control and treatment of Gram-negative bacterial infections. However, the long-term irrational use or even abuse of antibiotics has led to serious drug resistance of bacteria, which poses a serious threat to public health problems around the world. [0003] The most important drug resistance mechanism of bacteria is to produce β-lactamase, which can hydrolyze the lactam ring of β-lactam antibiotics to make antibiotics ineffective, thus producing resistance to antibiotics. According to the amino acid sequence of β-lactamase, β-lactamase can be divided into four types A-D, among which the ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4164A61K31/407A61P31/04
CPCA61K31/4164A61K31/407A61K2300/00Y02A50/30
Inventor 姜志辉石磊张冰何羡霞袁进杨琰杨晨关慧蔡敏捷蔡学究陈丽丹
Owner GENERAL HOSPITAL OF SOUTHERN THEATRE COMMAND OF PLA
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