Development of DNA polymerase IIIC inhibitors for the treatment of Gram-positive bacterial infections

Gram-positive (Gm⁺) bacteria express three distinct DNA polymerase-exonucleases. One of these, Gm⁺ DNA polymerase IIIC (DNA pol IIIC), is a highly conserved enzyme with little homology to mammalian DNA polymerase α and Gram-negative (Gm^–) DNA polymerases. DNA pol IIIC has been shown to be essential in the replicative DNA synthesis of Gm⁺ bacteria and, as such, represents an attractive, hitherto unexploited target for antimicrobial drug development. This article briefly reviews claims for DNA pol IIIC inhibitors for the treatment of bacterial infections, registered during the period 1996 – 2004. Biological data are sparse in these patents and few claims are backed up with in vivo animal model data. Although DNA pol IIIC has clearly been validated as a bona fide target for antimicrobial drug development, the effectiveness of such an agent in the clinic, particularly against resistant strains of Gm⁺ bacteria, remains to be determined.