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Development of potent chemical antituberculosis agents targeting Mycobacterium tuberculosis acetohydroxyacid synthase

Jung, In-Pil, Ha, Na-Reum, Lee, Sang-Choon, Ryoo, Sung-Weon, Yoon, Moon-Young
International journal of antimicrobial agents 2016 v.48 no.3 pp. 247-258
Mycobacterium tuberculosis, acetolactate synthase, active sites, binding sites, drugs, growth retardation, herbicides, hydrogen bonding, hydrophobicity, in vivo studies, inhibitory concentration 50, isoniazid, minimum inhibitory concentration, molecular models, multiple drug resistance, rifampicin, screening, tuberculosis
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.