Elucidation of the structure of DNA polymerase C (PolC) of multidrug resistant bacteria in complex with a novel class of antimicrobials

New antimicrobial therapies are urgently needed, and inhibitors of DNA polymerase C (PolC) are promising candidates for the treatment of multidrug-resistant Gram-positive bacteria. In this public private partnership, researchers from Leiden University Medical Center (LUMC) work together with US-based Acurx Pharmaceuticals LLC (‘Acurx’) to understand how these new antimicrobials work.

Antimicrobial resistant bacteria are a major threat to global health and pose a significant economic burden. Increasing resistance to multiple antimicrobials is observed, including so called last-resort antimicrobials. Up to 10M deaths annually projected in 2050 if not dealt with in a timely manner.

Several priority pathogens are Gram-positive bacteria; these include Clostridioides difficile (Cdiff), penicillin resistant Streptococcus pneumoniae (PRSP), methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE). A promising class of novel antimicrobials targets the PolC enzyme of these bacteria; the lead compound against Cdiff is currently in phase 3 clinical trials. In order to develop this class of antimicrobials further against other drug resistant pathogens, a better understanding of their mechanism of action is necessary. In this project, researchers want to generate structures of PolC’s from various pathogens in complex with clinical and pre-clinical inhibitors from Acurx using the state-of-the art infrastructure and expertise available at the LUMC.

The resulting structure(s) will shed light on how these compounds bind and inhibit the enzyme, and will guide rational design of novel inhibitors with improved binding and pharmacological properties.