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TitleBis-sulfonamido-2-phenylbenzoxazoles Validate the GroES/EL Chaperone System as a Viable Antibiotic Target.
Journal, issue, pagesJ Am Chem Soc, Vol. 146, Issue 30, Page 20845-20856, Year 2024
Publish dateJul 31, 2024
AuthorsJack Godek / Jared Sivinski / Edmond R Watson / Felicidad Lebario / Wenli Xu / Mckayla Stevens / Christopher J Zerio / Andrew J Ambrose / Xiaoyi Zhu / Carlee A Trindl / Donna D Zhang / Steven M Johnson / Gabriel C Lander / Eli Chapman /
PubMed AbstractWe recently reported on small-molecule inhibitors of the GroES/GroEL chaperone system as potential antibiotics against and the ESKAPE pathogens but were unable to establish GroES/GroEL as the ...We recently reported on small-molecule inhibitors of the GroES/GroEL chaperone system as potential antibiotics against 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 -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, . 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 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.
External linksJ Am Chem Soc / PubMed:39041457
MethodsEM (single particle)
Resolution3.26 - 3.97 Å
Structure data

45078

9c0b

EMDB-45078, PDB-9c0b:
E.coli GroEL + PBZ1587 inhibitor
Method: EM (single particle) / Resolution: 3.26 Å

45079

9c0c

EMDB-45079, PDB-9c0c:
E.coli GroEL apoenzyme
Method: EM (single particle) / Resolution: 3.41 Å

45080

9c0d

EMDB-45080, PDB-9c0d:
E.Faecium GroEL
Method: EM (single particle) / Resolution: 3.97 Å

EMDB-45098: E.coli GroEL + PBZ1587 inhibitor C1 reconstruction
Method: EM (single particle) / Resolution: 3.46 Å

Chemicals

PDB-1as6:
STRUCTURE OF NITRITE BOUND TO OXIDIZED ALCALIGENES FAECALIS NITRITE REDUCTASE AT CRYO TEMPERATURE

Source
  • escherichia coli (E. coli)
  • enterococcus faecium (bacteria)
KeywordsCHAPERONE / GroEL / Inhibitor / ANTIBIOTIC

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