Identification of Potential Inhibitors Targeting DNA Replication of Mycobacterium Tuberculosis

Overview

Bacterial antimicrobial resistance (AMR) represents a major public health threat, with projections estimating ten million deaths by 2050 due to AMR. Contributing factors to AMR include the misuse and overuse of antimicrobials in humans, animals, and the en vironment, along with the global spread of multidrug-resistant (MDR) bacteria and resistance genes across these areas. This crisis has driven research into alternative treatments and better antimicrobial stewardship to combat MDR pathogens. Among the challenges is the rise of drug-resistant Mycobacterium tuberculosis (Mtb), which necessitates the continuous development of new drugs effective against both multi- drug-resistant (MDR) and extensively drug -resistant (XDR) Mtb strains. Recent research has highlighted nargenicin, a natural product, for its ability to inhibit Mtb growth by targeting the bacterial DNA replication polymerase DnaE1. Nargenicin binds to the active site of DnaE1 in the presence of a DNA substrate. This discovery has paved the way for drug discovery efforts focused on Mtb DnaE1. Using an in -house developed platform, we have identified ten compounds that interact with the nargenicin binding pocket. These 'hit' compounds are currently undergoing structure-activity relationship (SAR) studies and medicinal chemistry modifications to develop lead compounds targeting DnaE1.