LAUSR

Acetohydroxyacid synthase (AHAS, EC 2.2.1.6) is the first enzyme in the branched chain amino acid biosynthesis pathway, is the target for more than 50 commercially available herbicides and is a promising target for antimicrobial drug discovery. Herein, we have expressed and purified AHAS from Candida auris, a newly identified human invasive fungal pathogen. Ten AHAS inhibiting herbicides have Ki values of < 2 M for this enzyme, with the most potent having Ki values of < 32 nM. Six of these compounds exhibited MIC50 values of < 5 M against C. auris (CBS10913 strain) grown in culture, with bensulfuron methyl (BSM) being fungicidal and the most potent (MIC50 of 0.090 M) in defined minimal media. The MIC50 value increase to 0.89 M in media enriched by the addition of branched chain amino acids at the expected concentration in the blood serum. The sessile MIC50 for BSM is 0.6 M. Thus, it is also an excellent inhibitor of the growth of C. auris biofilms. BSM is non-toxic in HEK-293 cells at concentrations >100 M and thus possesses a therapeutic index of >100. These data suggest that targeting AHAS is a viable strategy for treating C. auris infections.