A unique inhibitor conformation selectively targets the DNA polymerase PolC of Gram-positive priority pathogens
Open accessPublished version of a preprint
Abstract
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.
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Khanna, S. (2026) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2026.2634960 · Cited by 1 · see citing works
“Because PolC is absent from many gut anaerobic Gram-negative taxa, PolC inhibition offers a plausible route to a narrower ecological footprint than broad-spectrum agents [13].”
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Self-citation
- Authors
- Urem, M., Friggen, A. H., Musch, N., Silverman, M. H., Swain, C. J., Barbachyn, M. R., Mortin, L. I., Yu, X., DeLuccia, R. J., Lamers, M. H., & Smits, W. K.
- Affiliations
- Leiden University (NL)
- Calvin University (US)
- Corresponding author
- Lamers, Meindert H.
- Smits, Wiep Klaas
- ORCID
- Venue
- Nature Communications
- Published
- 2025-11-06
- Volume
- 16
- Issue
- 1
- Pages
- 9784-9784
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12592400
- OpenAlex
- W4415954572
- Cited by
- 2
- References
- 65
- Citations by year
- 2026: 2
- FWCI
- 0.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NEMI (184.034.014))
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Gram-positive pathogens, Enterococcus faecium, Clostridium difficile, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, antimicrobial resistance, priority pathogens
- MeSH terms
- Anti-Bacterial Agents, Bacterial Proteins, DNA-Directed DNA Polymerase, Enzyme Inhibitors, Humans, Clostridioides difficile, Enterococcus faecium, Cryoelectron Microscopy, Methicillin-Resistant Staphylococcus aureus
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