期刊
ACS INFECTIOUS DISEASES
卷 6, 期 11, 页码 2901-2912出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.0c00229
关键词
Candida auris; herbicides; biofilms; pathogenic fungus; AHAS inhibitor
资金
- National Health and Medical Research Council [1087713, 1147297]
- Therapeutic Innovation Australia (TIA)
- Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) programme
- ACRF
- National Health and Medical Research Council of Australia [1087713, 1147297] Funding Source: NHMRC
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 mu M for this enzyme, with the most potent having K-i values of <32 nM. Six of these compounds exhibited MIC50 values of <1 mu M against C. auris (CBS10913 strain) grown in culture, with bensulfuron methyl (BSM) being fungicidal and the most potent (MIC50 of 0.090 mu M) in defined minimal media. The MIC(50 )value increases to 0.90 mu 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 mu M. Thus, it is also an excellent inhibitor of the growth of C. auris biofilms. BSM is nontoxic in HEK-293 cells at concentrations >100 mu M 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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