Grant: Project Grant

According to the United Nations and the World Health Organization antimicrobial resistance is the largest threat to public health and economic growth. Currently, the greatest threat to human health derives from three multidrug-resistant Gram-negative priority pathogens that include Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae. These pathogens have become resistant to all or almost all of our antibiotics. Beta-lactam antibiotics are the most widely used class of antibacterial agents to combat bacterial infections. Beta-lactam antibiotics account for 65% of all prescriptions for injectable antibiotics in the United States. Current strategies to cope with beta-lactam antibiotic resistance are limited to inhibit beta-lactamase enzymes that hydrolyse the beta-lactam ring, thereby inactivating the drug. This can be achieved by combination therapy using a combination of a beta-lactam antibiotic and a beta-lactamase inhibitor. However, this approach does not address other resistance mechanisms that are prevalent in Gram-negative priority pathogens including outer membrane impermeability, efflux and porin suppression. To overcome these limitations we have developed beta-lactam antibiotic potentiators that restore efficacy in beta-lactam antibiotic/beta-lactamase inhibitor combinations against multidrug-resistant priority pathogens. The overall goal of this project is (i) to develop optimized and safe beta-lactam antibiotic potentiators that overcome resistance and extend the life of clinically approved beta-lactam antibiotic/beta-lactamase inhibitor combinations against multidrug-resistant priority pathogens and (ii) to demonstrate efficacy by protecting mice infected with beta-lactam antibiotic-resistant pathogens. Successful demonstration of efficacy and safety of the triple component combination in animal models will serve as a proof of principle to attract an industrial partner with the goal to commercialize novel anti-infective therapies.