AI Article Synopsis
- - DNA gyrase in Mycobacterium tuberculosis is a crucial enzyme that helps regulate DNA structure and is a promising target for developing new antibiotics.
- - Researchers discovered and improved a new class of inhibitors specifically targeting the ATPase domain of mycobacterial DNA gyrase, with Compound 17 proving to be the most effective.
- - Compound 17 showed strong inhibitory effects with low concentrations needed to disrupt bacterial growth, while also displaying no cardiotoxicity in tests, marking a significant advancement over previous drug candidates.
Article Abstract
DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase that ensures the regulation of DNA topology and has been genetically demonstrated to be a bactericidal drug target. We present the discovery and optimisation of a novel series of mycobacterial DNA gyrase inhibitors with a high degree of specificity towards the mycobacterial ATPase domain. Compound 5-fluoro-1-(2-(4-(4-(trifluoromethyl)benzylamino)piperidin-1-yl)ethyl)indoline-2,3-dione (17) emerged as the most potent lead, exhibiting inhibition of MTB DNA gyrase supercoiling assay with an IC50 (50% inhibitory concentration) of 3.6 ± 0.16 μM, a Mycobacterium smegmatis GyrB IC50 of 10.6 ± 0.6 μM, and MTB minimum inhibitory concentrations of 6.95 μM and 10 μM against drug-sensitive (MTB H37Rv) and extensively drug-resistant strains, respectively. Furthermore, the compounds did not show any signs of cardiotoxicity in zebrafish ether-à-go-go-related gene (zERG), and hence constitute a major breakthrough among the otherwise cardiotoxic N-linked aminopiperidine analogues.
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| http://dx.doi.org/10.1016/j.ijantimicag.2013.12.006 | DOI Listing |
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