Structural evidence for the covalent modification of FabH by 4,5-dichloro-1,2-dithiol-3-one (HR45)

Org Biomol Chem. 2017 Aug 2;15(30):6310-6313. doi: 10.1039/c7ob01396e.

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

  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / chemistry*
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism*
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / metabolism
  • Anti-Infective Agents / pharmacology*
  • Catalytic Domain
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / metabolism
  • Sulfhydryl Compounds / pharmacology*

Substances

  • 4,5-dichloro-1,2-dithiol-3-one
  • Anti-Infective Agents
  • Enzyme Inhibitors
  • Sulfhydryl Compounds
  • 3-ketoacyl-acyl carrier protein synthase III
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase