Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance

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 g-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.

Automated summary

The emergence of resistance to clinical antibiotics has prompted the development of a new antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S) defense system. Inhibitors of the bacterial cystathionine g-lyase (CSE) have been found to enhance the effectiveness of bactericidal antibiotics against major human pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. These inhibitors also disrupt bacterial tolerance, reduce biofilm formation, and decrease the number of persister bacteria surviving antibiotic treatment.