The Dual Mode of Antibacterial Action of the Synthetic Small Molecule DCAP Involves Lipid II Binding

J Am Chem Soc. 2024 Sep 11;146(36):24855-24862. doi: 10.1021/jacs.4c05138. Epub 2024 Aug 28.

Abstract

The synthetic small molecule DCAP is a chemically well-characterized compound with antibiotic activity against Gram-positive and Gram-negative bacteria, including drug-resistant pathogens. Until now, its mechanism of action was proposed to rely exclusively on targeting the bacterial membrane, thereby causing membrane depolarization, and increasing membrane permeability (Eun et al. 2012, J. Am. Chem. Soc. 134 (28), 11322-11325; Hurley et al. 2015, ACS Med. Chem. Lett. 6, 466-471). Here, we show that the antibiotic activity of DCAP results from a dual mode of action that is more targeted and multifaceted than previously anticipated. Using microbiological and biochemical assays in combination with fluorescence microscopy, we provide evidence that DCAP interacts with undecaprenyl pyrophosphate-coupled cell envelope precursors, thereby blocking peptidoglycan biosynthesis and impairing cell division site organization. Our work discloses a concise model for the mode of action of DCAP which involves the binding to a specific target molecule to exert pleiotropic effects on cell wall biosynthetic and divisome machineries.

MeSH terms

  • Anti-Bacterial Agents* / chemical synthesis
  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • Cell Wall / drug effects
  • Cell Wall / metabolism
  • Microbial Sensitivity Tests*
  • Molecular Structure
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Uridine Diphosphate N-Acetylmuramic Acid* / analogs & derivatives
  • Uridine Diphosphate N-Acetylmuramic Acid* / chemistry
  • Uridine Diphosphate N-Acetylmuramic Acid* / metabolism

Substances

  • Anti-Bacterial Agents
  • Uridine Diphosphate N-Acetylmuramic Acid
  • muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol
  • Small Molecule Libraries