Antibiotic-sparing strategies for treatment of bacterial infections

About This Grant

OVERALL ABSTRACT/SUMMARY The identification and development of effective antibiotics has over the last hundred years greatly enhanced human health; decreasing morbidity and mortality due to common infections, as well as preventing life-long sequelae from common infections including deafness from ear infections and neurological impairments from meningitis. However, the clinical arsenal of effective antibiotics is growing increasingly and alarmingly low, due to common pathogens becoming resistant to many antibiotics, including the pathogens of concern for this RFA; carbapenem-resistant Enterobacterales extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, carbapenem-resistant Acinetobacter baumannii, multidrug-resistant (MDR) Pseudomonas aeruginosa, drug-resistant Neisseria gonorrhoeae methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), drug-resistant Streptococcus pneumoniae and Clostridioides difficile. Without development of new therapeutics, strategies for treatment of infections with these pathogens and identification of new targets for therapeutic development, humans risk falling back in to the days where common infections were untreatable. Thus, this P01 seeks to fill this gap in therapeutic development through three scientific projects and one scientific core to combine the expertise of renowned researchers in bacterial pathogenesis, virulence factor identification and characterization, biochemistry, and powerful AI and protein design technologies, multi-omics analyses and medicinal chemistry. The overall goal of this P01 is to revolutionize the way important MDR infections are treated. The projects will together: i) develop transformative antibiotic-sparing therapies using revolutionary AI and protein design technologies that block disease by blocking host-pathogen interactions; and ii) mine microbe-treatment interactions to combat multidrug resistant polymicrobial catheter-associated urinary tract infection (CAUTI). All lead therapeutics and targets will be assessed in the Animal Core using powerful representative mouse models of disease including urinary tract infection (UTI), CAUTI, and skin and soft tissue infection (SSTI) all of which are diseases caused by a multitude of MDR organisms addressed in this RFA. The Scientific components will be supported by an Administrative Core to coordinate collaboration between the groups, outside experts, and NIH. While each Project stands on its own in making significant inroads into development of targets and therapeutics to combat the antibiotic resistance crisis, this P01 is specifically designed to be highly collaborative, widening the scope of projects to take advantage of the expertise of all of the leaders and teams.