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

• Antimicrobial resistance (AMR) has become a global crisis of growing proportions. • DNA polymerase IIIC (pol IIIC) is an unexploited target for low G + C Gram+ bacteria. • ACX-362E is the first pol IIIC inhibitor antimicrobial agent advanced to the clinic. • Pol IIIC inhibitors should not share cross-resistance with existing antibacterials. 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 N 7-substituted guanine drug candidate ACX-362E, now under clinical development for the treatment of Clostridioides difficile infection. [ABSTRACT FROM AUTHOR]