6dek
Crystal structure of Candida albicans acetohydroxyacid synthase catalytic subunit
Structural highlights
FunctionPublication Abstract from PubMedThe increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (Ki values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates. Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections.,Garcia MD, Chua SMH, Low YS, Lee YT, Agnew-Francis K, Wang JG, Nouwens A, Lonhienne T, Williams CM, Fraser JA, Guddat LW Proc Natl Acad Sci U S A. 2018 Sep 24. pii: 1809422115. doi:, 10.1073/pnas.1809422115. PMID:30249642[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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