A novel benzoxaborole works by targeting FabI in Escherichia coli

To combat the looming crisis of antimicrobial-resistant infections, there is an urgent need for novel antimicrobial discovery and drug target identification. The benzoxaborole series were previously identified as inhibitors of mycobacterial growth. Here, we demonstrate that a benzoxaborole is also active against the Gram negative bacterium, Escherichia coli in vitro. We isolated resistant mutants of E. coli and subjected them to whole genome sequencing. We found mutations in the enoyl acyl carrier protein FabI. Mutations mapped around the active center site located close to the co-factor binding site. This site partially overlaps with the binding pocket of triclosan, a known FabI inhibitor. Similar to triclosan, the interaction of the benzoxaborole with FabI was dependent on the co-factor NAD+. Identification of the target of this compound in E. coli provides scope for further development and optimization of this series for Gram negative pathogens.