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

• DOI: 10.1126/science.abd8377
• Publication Date: 2021-06-10T19:15:57Z
• Authors: 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
• Keywords: Models, Molecular; 0303 health sciences; Molecular Structure; Cystathionine gamma-Lyase; Drug Synergism; Drug Tolerance; Microbial Sensitivity Tests; Staphylococcal Infections; Crystallography, X-Ray; Anti-Bacterial Agents; 3. Good health; Molecular Docking Simulation; Small Molecule Libraries; Mice; 03 medical and health sciences; Biofilms; Drug Discovery; Drug Resistance, Bacterial; Pseudomonas aeruginosa; Animals; Pseudomonas Infections; Hydrogen Sulfide; Enzyme Inhibitors

Turning down tolerance

Persister cells, which are found in abundance in biofilms, adopt a quiescent state and survive antimicrobial treatments, seeding disease recurrence and incubating new resistance mutations. Building on work implicating the reactive small-molecule hydrogen sulfide in bacterial defense against antibiotics, Shatalin et al. conducted a structure-based screen for inhibitors of a bacterial hydrogen sulfide–producing enzyme and found a group of inhibitors that act through an allosteric mechanism (see the Perspective by Mah). These inhibitors potentiated bactericidal antibiotics in vitro and in mouse infection models. They also suppressed persister bacteria and disrupted biofilm formation. This strategy of taking out persister cells may be promising for treating recalcitrant infections and holding the line against drug-resistant bacteria.

Science , abd8377, this issue p. 1169 ; see also abj3062, p. 1153