Inhibitors of bacterial HS biogenesis targeting antibiotic resistance and tolerance.
Publication Type:Journal Article
Source:Science, Volume 372, Issue 6547, p.1169-1175 (2021)
Keywords:Animals, Anti-Bacterial Agents, Biofilms, Crystallography, X-Ray, Cystathionine gamma-Lyase, Drug Discovery, Drug Resistance, Bacterial, Drug Synergism, Drug Tolerance, Enzyme Inhibitors, Hydrogen Sulfide, Mice, Microbial Sensitivity Tests, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Pseudomonas aeruginosa, Pseudomonas Infections, Small Molecule Libraries, Staphylococcal Infections, Staphylococcus aureus
<p>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 (HS)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of HS in two major human pathogens, and , 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 HS as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.</p>