Acetohydroxyacid synthase (AHAS,
EC 2.2.1.6), 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. Thirteen AHAS inhibiting herbicides
have K
i values of <2 μM for this
enzyme, with the most potent having K
i values of <32 nM. Six of these compounds exhibited MIC50 values of <1 μM against C. auris (CBS10913
strain) grown in culture, with bensulfuron methyl (BSM) being fungicidal
and the most potent (MIC50 of 0.090 μM) in defined
minimal media. The MIC50 value increases to 0.90 μM
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 μM. Thus, it is also an excellent inhibitor
of the growth of C. auris biofilms. BSM is nontoxic
in HEK-293 cells at concentrations >100 μM and thus possesses
a therapeutic index of >100. These data suggest that targeting
AHAS
is a viable strategy for treating C. auris infections.
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