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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetolactate Synthase / antagonists & inhibitors*
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Acetolactate Synthase / chemistry
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Amino Acid Sequence
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Antifungal Agents / chemical synthesis*
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Antifungal Agents / chemistry
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Antifungal Agents / pharmacology
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Benzoates / chemical synthesis*
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Benzoates / chemistry
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Benzoates / pharmacology
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Candida albicans / drug effects*
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Candida albicans / enzymology
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Catalytic Domain
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Disk Diffusion Antimicrobial Tests
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Herbicides / pharmacology
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Microbial Sensitivity Tests
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Models, Molecular
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Molecular Sequence Data
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
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Sulfonylurea Compounds / chemical synthesis*
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Sulfonylurea Compounds / chemistry
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Sulfonylurea Compounds / pharmacology
Substances
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Antifungal Agents
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Benzoates
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Herbicides
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Recombinant Proteins
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Sulfonylurea Compounds
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ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl)sulfamoyl)benzoate
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Acetolactate Synthase