Grant: Project Grant

Antimicrobial resistance (AMR) is one of the leading global health threats facing humanity. We are exploring unconventional methods to identify and develop novel antimicrobial treatments. This research focuses on pathogenic Gram-negative bacteria, for which there is an immediate need for new therapeutics. Escherichia coli, in particular, is a high-priority pathogen estimated to be the leading cause of global deaths associated with AMR. Unfortunately, Gram-negative bacteria harbor a complex intrinsic antimicrobial resistome that has hindered the development of new antibiotic classes. Indeed, efflux pumps and the barrier functions of the outer membrane have been major hurdles in discovering new antibiotics targeting these organisms. This Project Grant holds promise in overcoming these historical challenges, providing a framework for developing new antimicrobials against E. coli. We will build upon our recent technological advances and novel findings to systematically explore E. coli efflux pump function and the cell envelope's formidable barrier functions, enabling the development of next-generation antimicrobial agents. Our goals are to (1) determine molecular features contributing to E. coli efflux and outer membrane permeation, (2) investigate whether efflux pumps are attractive antimicrobial targets, and (3) uncover novel cell envelope-associated targets and chemical leads for new antimicrobial development. Since E. coli is a leading cause of bloodstream infections and deaths associated with AMR, innovation in this field is urgently needed. Ultimately, our work will help identify and guide the development of new therapeutics to overcome AMR, while also shedding light on critical physiological processes.