Discovery and development of DNA polymerase IIIC inhibitors to treat Gram-positive infections

Bioorg Med Chem. 2019 Aug 1;27(15):3209-3217. doi: 10.1016/j.bmc.2019.06.017. Epub 2019 Jun 11.

Abstract

Despite the growing global crisis caused by antimicrobial drug resistance among pathogenic bacteria, the number of new antibiotics, especially new chemical class of antibiotics under development is insufficient to tackle the problem. Our review focuses on an emerging class of antibacterial therapeutic agents that holds a completely novel mechanism of action, namely, inhibition of bacterial DNA polymerase IIIC. The recent entry of this new class into human trials may herald the introduction of novel drugs whose novel molecular target precludes cross-resistance with existing antibiotic classes. This review therefore examines the evolution of DNA pol IIIC inhibitors from the discovery of 6-(p-hydroxyphenylazo)uracil (HPUra) in the 1960s to the development of current first-in-class N7-substituted guanine drug candidate ACX-362E, now under clinical development for the treatment of Clostridioides difficile infection.

Keywords: ACX-362E; Antibiotic resistance; C. difficile; DNA polymerase; Gram(+) bacteria; Pol IIIC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Clostridioides difficile / drug effects*
  • Clostridium Infections / drug therapy*
  • DNA Polymerase III / antagonists & inhibitors*
  • DNA Polymerase III / metabolism
  • Drug Discovery*
  • Humans
  • Microbial Sensitivity Tests
  • Nucleic Acid Synthesis Inhibitors / chemical synthesis
  • Nucleic Acid Synthesis Inhibitors / chemistry
  • Nucleic Acid Synthesis Inhibitors / pharmacology*
  • Uracil / analogs & derivatives
  • Uracil / chemistry
  • Uracil / pharmacology*

Substances

  • Nucleic Acid Synthesis Inhibitors
  • Uracil
  • DNA Polymerase III