THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates

Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2108244118. doi: 10.1073/pnas.2108244118.

Abstract

Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate-containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II-binding antibiotics, makes THCz promising scaffolds for development of cell wall-targeting antimicrobials.

Keywords: Streptococcus pneumoniae; antibiotic resistance; antimicrobials; cell wall biosynthesis; tetrahydrocarbazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Anti-Infective Agents / chemistry*
  • Anti-Infective Agents / pharmacology*
  • Bacteria / drug effects
  • Cell Wall / chemistry*
  • Cell Wall / drug effects*
  • Drug Resistance, Bacterial / drug effects
  • Lipids / chemistry*
  • Microbial Sensitivity Tests
  • N-Acetylmuramoyl-L-alanine Amidase
  • Peptidoglycan / biosynthesis
  • Polyisoprenyl Phosphates
  • Streptococcus pneumoniae / drug effects
  • Teichoic Acids / chemistry
  • Uridine Diphosphate N-Acetylmuramic Acid / analogs & derivatives

Substances

  • Anti-Bacterial Agents
  • Anti-Infective Agents
  • Lipids
  • Peptidoglycan
  • Polyisoprenyl Phosphates
  • Teichoic Acids
  • Uridine Diphosphate N-Acetylmuramic Acid
  • muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol
  • undecaprenyl pyrophosphate
  • N-Acetylmuramoyl-L-alanine Amidase