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

Autor: Shatalin K; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Nuthanakanti A; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Kaushik A; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Shishov D; Gero LLC, Moscow, Russia., Peselis A; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Shamovsky I; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Pani B; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Lechpammer M; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Vasilyev N; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Shatalina E; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Rebatchouk D; Ellyris LLC, Union, NJ 07083, USA., Mironov A; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Moscow 119991, Russia., Fedichev P; Gero LLC, Moscow, Russia., Serganov A; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA., Nudler E; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. evgeny.nudler@nyulangone.org.; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2021 Jun 11; Vol. 372 (6547), pp. 1169-1175.
DOI: 10.1126/science.abd8377
Abstrakt: 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 (H 2 S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H 2 S 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 H 2 S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.
(Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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