2. Academic Validation
  3. Bis-sulfonamido-2-phenylbenzoxazoles Validate the GroES/EL Chaperone System as a Viable Antibiotic Target

Bis-sulfonamido-2-phenylbenzoxazoles Validate the GroES/EL Chaperone System as a Viable Antibiotic Target

  • J Am Chem Soc. 2024 Jul 31;146(30):20845-20856. doi: 10.1021/jacs.4c05057.
Jack Godek 1,  Jared Sivinski 2,  Edmond R Watson 3,  Felicidad Lebario 1,  Wenli Xu 2,  Mckayla Stevens 4,  Christopher J Zerio 2,  Andrew J Ambrose 2,  Xiaoyi Zhu 1,  Carlee A Trindl 1,  Donna D Zhang 5,  Steven M Johnson 4,  Gabriel C Lander 3,  Eli Chapman 1
Affiliations

Affiliations

  • 1 College of Medicine, Department of Pharmacology and Therapeutics, Center for Inflammation Science and Systems Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, 130 Scripps Way, Jupiter, Florida 33458, United States.
  • 2 College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • 3 Department of Integrative Structural and Computational Biology, Scripps Research, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
  • 4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, Indiana 46202, United States.
  • 5 The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Center for Inflammation Science and Systems Medicine, 130 Scripps Way, Jupiter, Florida 33458, United States.
PMID: 39041457 DOI: 10.1021/jacs.4c05057
Abstract

We recently reported on small-molecule inhibitors of the GroES/GroEL chaperone system as potential Antibiotics against Escherichia coli and the ESKAPE pathogens but were unable to establish GroES/GroEL as the cellular target, leading to cell death. In this study, using two of our most potent bis-sulfonamido-2-phenylbenzoxazoles (PBZs), we established the binding site of the PBZ molecules using cryo-EM and found that GroEL was the cellular target responsible for the mode of action. Cryo-EM revealed that PBZ1587 binds at the GroEL ring-ring interface (RRI). A cellular reporter assay confirmed that PBZ1587 engaged GroEL in cells, but cellular rescue experiments showed potential off-target effects. This prompted us to explore a closely related analogue, PBZ1038, which is also bound to the RRI. Biochemical characterization showed potent inhibition of Gram-negative chaperonins but much lower potency of chaperonin from a Gram-positive organism, Enterococcus faecium. A cellular reporter assay showed that PBZ1038 also engaged GroEL in cells and that the cytotoxic phenotype could be rescued by a chromosomal copy of E. faecium GroEL/GroES or by expressing a recalcitrant RRI mutant. These data argue that PBZ1038's antimicrobial action is exerted through inhibition of GroES/GroEL, validating this chaperone system as an Antibiotic target.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163887
    Antimicrobial Agents