title: Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase.
abstract: The sulfonylurea herbicides exert their activity by inhibiting plant acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway. It has previously been shown that if the gene for AHAS is deleted in Candida albicans , attenuation of virulence is achieved, suggesting AHAS as an antifungal drug target. Herein, we have cloned, expressed, and purified C. albicans AHAS and shown that several sulfonylureas are inhibitors of this enzyme and possess antifungal activity. The most potent of these compounds is ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl)sulfamoyl)benzoate (10c), which has a K(i) value of 3.8 nM for C. albicans AHAS and an MIC₉₀ of 0.7 μg/mL for this fungus in cell-based assays. For the sulfonylureas tested there was a strong correlation between inhibitory activity toward C. albicans AHAS and fungicidal activity, supporting the hypothesis that AHAS is the target for their inhibitory activity within the cell.
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Lee
authors.forename: Chang-Jun
authors.initials: CJ
authors.lastname: Cui
authors.forename: Eve W L
authors.initials: EW
authors.lastname: Chow
authors.forename: Nason
authors.initials: N
authors.lastname: Pue
authors.forename: Thierry
authors.initials: T
authors.lastname: Lonhienne
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Wang
authors.forename: James A
authors.initials: JA
authors.lastname: Fraser
authors.forename: Luke W
authors.initials: LW
authors.lastname: Guddat
mesh_terms: D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D020134:Catalytic Domain; D052978:Disk Diffusion Antimicrobial Tests; D006540:Herbicides / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D001565:Benzoates; D006540:Herbicides; D011994:Recombinant Proteins; D013453:Sulfonylurea Compounds; C579727:ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl)sulfamoyl)benzoate; D000095:Acetolactate Synthase