Antibiotic-resistant bacterial infections that are no longer sensitive to our life saving antibiotic arsenal are a looming catastrophe and like the recent COVID-19 crisis, will have dire consequences for human health if we are not prepared. This proposal leverages basic science findings for development of antibiotic-sparing medicines with impact on treatment for most pathogens designated threats to human health by the CDC. Projects 1 and 2 target multi-drug resistant (MDR) Gram-negative pathogens that express adhesive pili required for colonization and infection in the host habitats involved in acute and chronic/recurrent urinary tract infections (UTIs) and catheter-associated UTIs (CAUTIs), including MDR Acinetobacter, carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. Project 2 expands on this list to include other Gram-negative pathogens of concern. Since UTIs account for ~10% of antibiotic use in humans, the development of antibiotic-sparing therapeutics will not only allow treatment of antibiotic-resistant infections, but by reducing the use of current antibiotics, will decrease selective pressures for resistance. Project 1 is focused on neutralizing bacterial pilus adhesins using glycomimetics designed in CORE 1 and mAbs developed in CORE 2 that will block critical interactions between bacterial adhesins and their host ligands. Glycomimetics have shown great promise in neutralizing chaperone/usher pathway (CUP) adhesins in vivo to treat disease. For example, mannosides, which neutralize uropathogenic E. coli (UPEC) adhesin FimH, are potent therapeutics for treating and preventing UTI, since FimH is required by UPEC to colonize the bladder. In collaboration with GlaxoSmithKline a mannoside has been selected to proceed into Phase 1a/1b clinical trials, thus validating the potential of this strategy. Therapeutic mAbs have not yet been fully harnessed for treating infectious diseases. With antibiotic resistance on the rise, it is time to apply this strategy. Project 1 will also target a sortase-assembled pilus adhesin of Gram-positive enterococci, which causes CAUTIs and is often MDR. Project 2 will use similar tools to focus on the CUP machinery that assembles the Gram-negative adhesins in Project 1 at the tip of pilus fibers. Project 3 will target all Gram- positive species identified by the CDC as significant threats by furthering the development of GmPcides, a novel family of ring-fused 2-pyridone compounds that are bactericidal against a broad spectrum of Gram- positive species. The COREs will be fully integrated with the Scientific Projects providing computational and synthetic medicinal chemistry in the development of small molecule therapeutics (CORE 1) and the application of high throughput mAb generation against bacterial proteins (CORE 2). The combined knowledge, expertise and successes of the Leaders of the Projects and Cores will lead to the development of antibiotic-sparing therapeutics for treatment of the growing number of antibiotic-resistant pathogens to stave off the return to the pre-antibiotic era when common infections were essentially untreatable.
Antibiotic resistance is a looming crisis, with the real possibility of common infections becoming untreatable if we do not increase our ability to combat antibiotic resistant pathogens. This U19 will target the development of antibiotic-sparing therapeutics including rationally designed glycomimetics, peptidomimetics and pyridones, as well as mAbs, that can inhibit key host-pathogen interactions and affect the viability of pathogens that are both antibiotic-sensitive and antibiotic-resistant. Thus, this U19 has great potential to impact human health by combating the rising antibiotic resistance problem.
