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<p>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 <i>Clostridioides difficile</i> infections, and related inhibitors are being developed for systemic treatment of infections with methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and vancomycin-resistant enterococci (VRE). Here, we present the cryo-electron microscopy structures of <i>Enterococcus faecium</i> 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 <i>C. difficile</i>. 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月6日

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  • 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,
  • Wiep Klaas Smits

摘要

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.