A Novel Inhibitor of Acetohydroxyacid Synthase with Pan-antimycobacterial Activity

Acetohydroxyacid synthase (AHAS), an enzyme found in microorganisms and plants but absent in animals, has emerged as a promising target for the development of antibacterial drugs.AHAS is the first enzyme in the branched-chain amino acid biosynthesis pathway.Inhibiting AHAS is a compelling strategy, particularly against mycobacteria.Mycobacteria replicate within phagocytes, where amino acid availability is severely restricted, making AHAS inhibitors particularly attractive candidates for combating mycobacterial infections.While Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTM) strains share significant genetic homology, current anti-Mtb drugs are ineffective against NTM disease.Consequently, the development of novel antibiotics capable of effectively inhibiting NTM growth is crucial in the face of increasing global NTM infection.In this present study, we evaluated the antimycobacterial effects of an AHAS-targeted synthetic compound, K13787, which is targeted against AHAS, on M. abscessus.We found that K13787 exhibited an inhibitory effect on the growth of M. abscessus in vitro and in vivo, and it also improved the survival of M. abscessus-infected mice.These findings suggest that the recently identified compound K13787, which targets AHAS, has the potential to serve as a lead compound in the development of novel antimycobacterial agents for the treatment of M. abscessus infection.In summary, the results of this study indicate that various compounds that inhibit AHAS, including K13787, are promising candidates for treatment of NTM infection.