A unique inhibitor conformation selectively targets the DNA polymerase PolC of Gram-positive priority pathogens

Mia 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 () and Wiep Klaas Smits ()
Additional contact information
Mia Urem: Leiden University Medical Center
Annemieke H. Friggen: Leiden University Medical Center
Nina Musch: Leiden University Medical Center
Michael H. Silverman: Inc.
Christopher J. Swain: Inc.
Michael R. Barbachyn: Calvin University
Lawrence I. Mortin: Inc.
Xiang Yu: Inc.
Robert J. DeLuccia: Inc.
Meindert H. Lamers: Leiden University Medical Center
Wiep Klaas Smits: Leiden University Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65324-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65324-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65324-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().