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TitleA unique inhibitor conformation selectively targets the DNA polymerase PolC of Gram-positive priority pathogens.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 9784, Year 2025
Publish dateNov 6, 2025
AuthorsMia Urem / Annemieke H Friggen / Nina Musch / Michael H Silverman / Christopher J Swain / Michael R Barbachyn / Lawrence I Mortin / Xiang Yu / Robert J DeLuccia / Meindert H Lamers / Wiep Klaas Smits /
PubMed AbstractInfections with antimicrobial resistant pathogens are a major threat to human health. Inhibitors of the replicative polymerase PolC are a promising novel class of antimicrobials against Gram-positive ...Infections with antimicrobial resistant pathogens are a major threat to human health. Inhibitors of the replicative polymerase PolC are a promising novel class of antimicrobials against Gram-positive pathogens, but the structural basis for their activity remains unknown. The first-in-class PolC-targeting antimicrobial, ibezapolstat, is a guanine analogue in late-stage clinical development for the treatment of Clostridioides difficile infections, and related inhibitors are being developed for systemic treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Here, we present the cryo-electron microscopy structures of Enterococcus faecium PolC bound to DNA and in complex with ibezapolstat or the previously-undescribed inhibitor ACX-801. Both inhibitors form base-pairing interactions with the DNA in the active site, thereby competing with incoming dGTP nucleotides. We identify a crucial susceptibility determinant in PolC that is conserved in other organisms, such as C. difficile. This is explained by an unusual non-planar conformation of the inhibitors that induce a binding pocket in PolC. By combining structural, biochemical, bioinformatic and genetic analyses, this work lays the foundation for the rational development of an innovative class of antimicrobials against Gram-positive priority pathogens.
External linksNat Commun / PubMed:41198680 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.2 Å
Structure data

53270

9qpc

EMDB-53270, PDB-9qpc:
DNA polymerase with inhibitor
Method: EM (single particle) / Resolution: 2.8 Å

53319

9qrl

EMDB-53319, PDB-9qrl:
DNA polymerase with inhibitor #2
Method: EM (single particle) / Resolution: 3.2 Å

53320

9qrn

EMDB-53320, PDB-9qrn:
DNA polymerase without DNA or inhibitor
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

PDB-1i88:
CHALCONE SYNTHASE (G256V)

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

PDB-1i9t:
CRYSTAL STRUCTURE OF THE OXIDIZED RNA TRIPHOSPHATASE DOMAIN OF MOUSE MRNA CAPPING ENZYME

Source
  • enterococcus faecium (bacteria)
  • escherichia coli (E. coli)
KeywordsDNA BINDING PROTEIN / DNA polymerase / inhibitor complex

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