Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance

Konstantin Shatalin, Ashok Nuthanakanti, Abhishek Kaushik, Dmitry Shishov, Alla Peselis, Ilya Shamovsky, Bibhusita Pani, Mirna Lechpammer, Nikita Vasilyev, Elena Shatalina, Dmitri Rebatchouk, Alexander Mironov, Peter Fedichev, Alexander Serganov, Evgeny Nudler

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)1169-1175
Number of pages7
JournalScience
Volume372
Issue number6540
DOIs
StatePublished - Apr 23 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Inhibitors of bacterial H<sub>2</sub>S biogenesis targeting antibiotic resistance and tolerance'. Together they form a unique fingerprint.

Cite this