2. Academic Validation
  3. Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance

Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance

  • Science. 2021 Jun 11;372(6547):1169-1175. doi: 10.1126/science.abd8377.
Konstantin Shatalin # 1,  Ashok Nuthanakanti # 1,  Abhishek Kaushik 1,  Dmitry Shishov 2,  Alla Peselis 1,  Ilya Shamovsky 1,  Bibhusita Pani 1,  Mirna Lechpammer 1,  Nikita Vasilyev 1,  Elena Shatalina 1,  Dmitri Rebatchouk 3,  Alexander Mironov 4,  Peter Fedichev 2,  Alexander Serganov 1,  Evgeny Nudler 5 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
  • 2 Gero LLC, Moscow, Russia.
  • 3 Ellyris LLC, Union, NJ 07083, USA.
  • 4 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Moscow 119991, Russia.
  • 5 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. evgeny.nudler@nyulangone.org.
  • 6 Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
  • # Contributed equally.
PMID: 34112687 DOI: 10.1126/science.abd8377
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-170028
    bCSE Inhibitor