Development of potent chemical antituberculosis agents targeting Mycobacterium tuberculosis acetohydroxyacid synthase
- Title
- Development of potent chemical antituberculosis agents targeting Mycobacterium tuberculosis acetohydroxyacid synthase
- Author
- 윤문영
- Keywords
- Mycobacterium tuberculosis; Acetohydroxyacid synthase; Potent inhibitor; Drug-resistant TB; Cytotoxicity; Molecular docking
- Issue Date
- 2016-09
- Publisher
- ELSEVIER SCIENCE BV
- Citation
- INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, v. 48, NO. 3, Page. 247-258
- Abstract
- Mycobacterium tuberculosis acetohydroxyacid synthase (MTB-AHAS) has been suggested as a crucial target for antibacterial agents. High-throughput screening of a chemical library was performed to identify potent new inhibitors of MTB-AHAS. Among the 6800 tested compounds, 15 were identified as potent inhibitors, exhibiting >80-90% inhibition of in vitro MTB-AHAS activity at a fixed concentration of 20 mu M. Five compounds belonging to the triazolopyrimidine structural class showed greater inhibition potency, with a half-maximum inhibition concentration (IC50 value) in the low micromolar range (0.4-1.24 mu M). Furthermore, potent inhibitors demonstrated non-competitive, uncompetitive or mixed-competitive inhibition. Molecular docking experiments with these potent chemicals using a homology model of MTB-AHAS indicated hydrophobic and hydrogen bond interactions with some key herbicide binding site residues with binding energies (Delta G) of -8.04 to -10.68 Kcal/mol, respectively. The binding modes were consistent with inhibition mechanisms, as the chemicals were oriented outside the active site. Importantly, these potent inhibitors demonstrated significant growth inhibition of various clinically isolated multidrug-resistant and extensively drug-resistant M. tuberculosis strains, with 50% minimum inhibitory concentrations (MIC50 values) ranging from 0.2 mu g/mL to 0.8 mu g/mL, which resemble the MICs of conventional drugs for tuberculosis (isoniazid, 0.1 mu g/mL; rifampicin, 0.4 mu g/mL). Thus, the identified potent inhibitors show potential as scaffolds for further in vivo studies and might provide an impetus for the development of strong antituberculosis agents targeting MTB-AHAS. (C) 2016 Published by Elsevier B.V.
- URI
- https://www.sciencedirect.com/science/article/pii/S0924857916301443?via%3Dihubhttps://repository.hanyang.ac.kr/handle/20.500.11754/80448
- ISSN
- 0924-8579; 1872-7913
- DOI
- 10.1016/j.ijantimicag.2016.04.031
- Appears in Collections:
- COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > CHEMISTRY(화학과) > Articles
- Files in This Item:
There are no files associated with this item.
- Export
- RIS (EndNote)
- XLS (Excel)
- XML