期刊
PHARMACEUTICS
卷 13, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics13010006
关键词
antibacterial; ciprofloxacin; DNA gyrase; dual inhibitor; hybrid
资金
- Slovenian Research Agency [P1-0208]
- European Research Council H2020-ERC-2014-CoG [648364]
- 'Celzott Lendulet' Programme of the Hungarian Academy of Sciences [LP-2017-10/2017, KKP 126506, GINOP-2.3.2-15-2016-00014, GINOP-2.3.2-15-2016-00020, GINOP-2.3.3-15-2016-00001, EFOP 3.6.3-VEKOP-16-2017-00009]
- New National Excellence Programme of the Ministry for Innovation and Technology [UNKP-20-3]
- Boehringer Ingelheim Fonds
- European Research Council (ERC) [648364] Funding Source: European Research Council (ERC)
The discovery of multi-targeting ligands for bacterial enzymes is crucial in combating antimicrobial resistance. The designed hybrids effectively inhibit DNA gyrase and show antibacterial activity against Gram-negative pathogens, providing a promising therapeutic strategy.
The discovery of multi-targeting ligands of bacterial enzymes is an important strategy to combat rapidly spreading antimicrobial resistance. Bacterial DNA gyrase and topoisomerase IV are validated targets for the development of antibiotics. They can be inhibited at their catalytic sites or at their ATP binding sites. Here we present the design of new hybrids between the catalytic inhibitor ciprofloxacin and ATP-competitive inhibitors that show low nanomolar inhibition of DNA gyrase and antibacterial activity against Gram-negative pathogens. The most potent hybrid 3a has MICs of 0.5 mu g/mL against Klebsiella pneumoniae, 4 mu g/mL against Enterobacter cloacae, and 2 mu g/mL against Escherichia coli. In addition, inhibition of mutant E. coli strains shows that these hybrid inhibitors interact with both subunits of DNA gyrase (GyrA, GyrB), and that binding to both of these sites contributes to their antibacterial activity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据