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Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections.
Garcia, Mario D; Chua, Sheena M H; Low, Yu-Shang; Lee, Yu-Ting; Agnew-Francis, Kylie; Wang, Jian-Guo; Nouwens, Amanda; Lonhienne, Thierry; Williams, Craig M; Fraser, James A; Guddat, Luke W.
Afiliação
  • Garcia MD; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Chua SMH; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Low YS; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Lee YT; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Agnew-Francis K; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Wang JG; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Nouwens A; State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
  • Lonhienne T; National Pesticide Engineering Research Center, College of Chemistry, Nankai University, Tianjin 300071, China.
  • Williams CM; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Fraser JA; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Guddat LW; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Proc Natl Acad Sci U S A ; 115(41): E9649-E9658, 2018 10 09.
Article em En | MEDLINE | ID: mdl-30249642
The 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Acetolactato Sintase / Candida albicans / Candidíase / Proteínas Fúngicas / Criptococose / Cryptococcus neoformans / Antifúngicos Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Acetolactato Sintase / Candida albicans / Candidíase / Proteínas Fúngicas / Criptococose / Cryptococcus neoformans / Antifúngicos Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article