Acetohydroxyacid synthase (AHAS) is the first enzyme in the branched chain amino acid biosynthesis pathway. This pathway is present only in plants, bacteria and fungi making it an excellent target for drug discovery. In total, 50 commercial herbicides have been developed that target this enzyme and are now in world-wide use for crop protection. We have used X-ray crystallography and kinetic studies to show precisely the mode of action of these herbicides [1, 2]. Intriguingly, they act by a process of slow accumulative inhibition resulting in the modification of the enzymes’ cofactors ThDP and FAD and accelerate a side reaction leading to the production of peracetate [3]. We have shown that AHAS inhibitors are powerful inhibitors of Candida albicans AHAS (Ki~800 pM). In cell culture these compounds have MIC values as low as 0.03 ug/mL whilst in mice infected with Candida albicans they have the ability to completely clear infection from the lungs [4].
References
[1] Lonhienne, T., et al., Commercial herbicides can trigger the oxidative inactivation of acetohydroxyacid synthase.Angew Chem Int Ed Engl, 2016. 55(13): p. 4247-4251.
[2] Garcia, M.D., et al., Comprehensive understanding of acetohydroxyacid synthase inhibition by different herbicide families.Proc Natl Acad Sci U S A, 2017. 114(7): p. E1091-E1100.
[3] Lonhienne, T., et al., Structural insights into the mechanism of inhibition of AHAS by herbicides.Proc Natl Acad Sci USA, 2018. 115E1945-E1954
[4] Garcia, M., et al., Commercial AHAS inhibiting herbicides are promisingdrug leads for the treatment of human fungal pathogenic infections.Proc. Natl. Acad. Sci. USA, doi.org/10.1073/pnas.1809422115