PDBsum entry 7mcp

Lyase

PDB id: 7mcp

Contents

Protein chains

380 a.a.

Ligands

PLP ×2

GOL ×4

Metals

_NA ×6

Waters ×496

References listed in PDB file

Key reference

• Title: Inhibitors of bacterial h₂s biogenesis targeting antibiotic resistance and tolerance.
• Authors: K.Shatalin, A.Nuthanakanti, A.Kaushik, D.Shishov, A.Peselis, I.Shamovsky, B.Pani, M.Lechpammer, N.Vasilyev, E.Shatalina, D.Rebatchouk, A.Mironov, P.Fedichev, A.Serganov, E.Nudler.
• Ref.: Science, 2021, 372, 1169-1175.
• PubMed id: 34112687

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.