Inhibitors of acetohydroxyacid synthase as promising agents against non-tuberculous mycobacterial diseases.

Acetohydroxyacid synthase (AHAS), exclusively present in microorganisms and plants, is a promising target for several herbicides due to its catalytic role in the branched-chain amino acid biosynthetic pathway. Previous studies have shown that K13787, a pyrazolopyrimidine sulfonamide AHAS inhibitor, was moderately effective against pulmonary infection caused by M. tuberculosis and nontuberculous mycobacteria (NTM). In this study, we synthesized various structural derivatives of K13787 based on the molecular docking studies and assessed their MICs against mycobacteria species. Among the synthetic compounds screened, K13787, along with KNT2077 and KNT2099, exhibited inhibitory efficacy against M. avium and M. abscessus, including CLR-resistant NTM species. Notably, these compounds displayed a synergistic effect (FIC ≤ 0.5) when combined with CLR against M. avium and M. abscessus. Our findings suggest that these newly identified AHAS-targeted compounds hold promise as lead candidates for novel antimycobacterial agents against NTM infections. Considering the structure-activity relationship, K13787, KNT2077, and KTN2099 emerge as potential treatments for NTM species.