Rational design and synthesis of small molecule inhibitors targeting unique pathogenic mechanisms in Gram- and Gram+ bacteria important in UTI

PROJECT SUMMARY/ABSTRACT: The current COVID-19 pandemic has shown us first-hand the dire consequences that being unprepared for potential health crises can bring, and has reminded society as a whole of the disastrous impact that infectious diseases can still have on overall human health and society. The emergence and rapid dissemination of antibiotic-resistant bacterial pathogens poses a severe looming global crisis and an increasingly dire threat to overall human health. This U19 seeks to combat this growing crisis through the generation and development of antibiotic-sparing therapeutics that are specifically targeted against key virulence mechanisms used by pathogenic bacteria. CORE 1 will be fully integrated, working with the each of the Scientific Projects providing computational and synthetic medicinal chemistry in the design, creation and characterization of small molecule therapeutics that will target common bacterial virulence mechanisms and viability to treat causative agents of infections, regardless of the pathogen's antibiotic susceptibility profiles. With Project 1, this CORE will produce small molecule glycoside-based bacterial adhesin lectin domain antagonists that are critical for E. coli, Klebsiellsa, Acinetobacter and Enterococcus to cause urinary tract infections (UTIs) and catheter-associated UTIs. This work is based on a deep understanding of the structures, ligands and biological functions of uropathogen adhesins. This team has already successfully developed rationally-designed glycosides. Notably, a candidate FimH antagonist called a mannoside, developed by CORE leader Dr. Janetka, has been approved for Phase 1a/1b clinical trials in humans. This is a clear validation of the approaches in this proposal. With Project 2, we will target the assembly machinery of the ubiquitous chaperone usher pathway (CUP) systems, which a wide variety of Gram-negative bacteria, including those of interest to this RFA, use to elaborate adhesive pilus on their surface to mediate distinct binding to particular host surfaces and tissues. Ring fused 2-pyridones called pilicides have already been developed that act as peptidomimetic inhibitors of the chaperone CUP system. We will expand on these studies to target the outer membrane assembly protein, the usher, to block its function and increase the permeability of the outer membrane to other antibiotics. With Project 3, we seek to expand our collection of 2- pyridone based compounds named GmPcides (Gram positive cides), which we have found are bactericidal against a wide variety of Gram-positive pathogens that cause healthcare associated infections. CORE leader Dr. Almqvist's expertise in designing and optimizing these compounds will be critical for the successful completion of projects 2 (pilicides) and 3 (GmPcides). Core leaders Dr. Janetka and Dr. Almqvist have extensive expertise in synthetic organic chemistry, and in the rational design and synthesis of therapeutics. The combined knowledge and past success from these two groups will provide strong chemistry support and drug discovery leadership to all 3 projects of this U19 proposal.