Abstract
We use mass spectrometry analysis and molecular modelling to show the established antimicrobial inhibitor 4,5-dichloro-1,2-dithiol-3-one (HR45) acts by forming a covalent adduct with the target β-ketoacyl-ACP synthase III (FabH). The 5-chloro substituent directs attack of the essential active site thiol (C112) via a Michael-type addition elimination reaction mechanism.
MeSH terms
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / chemistry*
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism*
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Anti-Infective Agents / chemistry
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Anti-Infective Agents / metabolism
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Anti-Infective Agents / pharmacology*
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Catalytic Domain
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Models, Molecular
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Sulfhydryl Compounds / chemistry
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Sulfhydryl Compounds / metabolism
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Sulfhydryl Compounds / pharmacology*
Substances
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4,5-dichloro-1,2-dithiol-3-one
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Anti-Infective Agents
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Enzyme Inhibitors
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Sulfhydryl Compounds
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3-ketoacyl-acyl carrier protein synthase III
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase