Inhibitors of bacterial H 2 S biogenesis targeting antibiotic resistance and tolerance

Science. 2021 Jun 11;372(6547):1169-1175. doi: 10.1126/science.abd8377.

Abstract

Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Biofilms
  • Crystallography, X-Ray
  • Cystathionine gamma-Lyase / antagonists & inhibitors*
  • Cystathionine gamma-Lyase / chemistry
  • Cystathionine gamma-Lyase / genetics
  • Cystathionine gamma-Lyase / metabolism
  • Drug Discovery
  • Drug Resistance, Bacterial
  • Drug Synergism
  • Drug Tolerance
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Hydrogen Sulfide / metabolism*
  • Mice
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Pseudomonas Infections / drug therapy
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / enzymology
  • Pseudomonas aeruginosa / genetics
  • Pseudomonas aeruginosa / growth & development
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology
  • Staphylococcal Infections / drug therapy
  • Staphylococcal Infections / microbiology
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / enzymology
  • Staphylococcus aureus / genetics
  • Staphylococcus aureus / growth & development

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide