title: Development of potent chemical antituberculosis agents targeting Mycobacterium tuberculosis acetohydroxyacid synthase.
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 µM. 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 µM). 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 (ΔG) 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 µg/mL to 0.8 µg/mL, which resemble the MICs of conventional drugs for tuberculosis (isoniazid, 0.1 µg/mL; rifampicin, 0.4 µg/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.
authors.affiliation: Department of Chemistry, Institute of Natural Sciences, Hanyang University, Seoul 04763, South Korea.
authors.forename: In-Pil
authors.initials: IP
authors.lastname: Jung
authors.affiliation: Department of Chemistry, Institute of Natural Sciences, Hanyang University, Seoul 04763, South Korea.
authors.forename: Na-Reum
authors.initials: NR
authors.lastname: Ha
authors.affiliation: Department of Chemistry, Institute of Natural Sciences, Hanyang University, Seoul 04763, South Korea.
authors.forename: Sang-Choon
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Korean Institute of Tuberculosis, 168-5 Osong Saengmyeong 4-ro, Osong, Cheongju 28158, South Korea.
authors.forename: Sung-Weon
authors.initials: SW
authors.lastname: Ryoo
authors.affiliation: Department of Chemistry, Institute of Natural Sciences, Hanyang University, Seoul 04763, South Korea. Electronic address: myyoon@hanyang.ac.kr.
authors.forename: Moon-Young
authors.initials: MY
authors.lastname: Yoon
mesh_terms: D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000995:Antitubercular Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000302:isolation & purification; D011485:Protein Binding; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D000095:Acetolactate Synthase
keywords: Acetohydroxyacid synthase; Cytotoxicity; Drug-resistant TB; Molecular docking; Mycobacterium tuberculosis; Potent inhibitor