With dire predictions of antibiotic resistance reaching a tipping point, it is imperative that novel, antibiotic-sparing medicines are developed to avoid facing increasing deaths due to previously treatable common infections. This project is focused on this mission by elucidating potential therapeutic targets critical in host-pathogen interactions for urinary tract infections (UTI), one of the most common infections leading to significant antibiotic use and economic burden. Over 11 million women suffer from UTIs in the U.S. per year. Further, 20-30% of women diagnosed with a UTI will experience a recurrent UTI (rUTI) in the following months, resulting in a serious deterioration in the quality of life through pain, discomfort, disruption of daily activities, and increased healthcare cost. This problem is exacerbated by rising antimicrobial resistance among uropathogenic Escherichia coli (UPEC), the cause of over 80% of uncomplicated UTIs. Rates of antibiotic resistance are confounding UTI treatment for millions of women annually. One critical aspect of uropathogenesis is the ability of bacteria to bind to host tissues to establish an infection or colonization. Gram-negative bacteria typically utilize adhesive chaperone usher pathway (CUP) pili, tipped with adhesins that bind to receptors with stereochemical specificity, mediating host and tissue tropisms. Pilus adhesins are two-domain molecules consisting of a C-terminal pilin domain that links the adhesin to the pilus tip and an N-terminal receptor-binding domain. The pangenome of E. coli alone encodes thirty-eight distinct CUP pilus types and single E. coli genomes encode as many as 16, each likely mediating colonization of a particular habitat. However, only a handful of UPEC adhesins have been investigated to date. Each of them play critical roles in particular niches. FimH mediates critical binding to mannose residues on bladder tissue to promote invasion into superficial facet cells during acute cystitis; FmlH mediates binding to galactose moieties on inflamed bladder epithelial tissue during chronic cystitis; PapG mediates binding to human kidney during pyelonephritis; and UclD mediates colonization of the gut where UPEC forms a reservoir. Catheterization increases the susceptibility of the urinary tract to infection with a wider variety of strains, including Acinetobacter baumanii resulting in increasingly common multidrug resistant catheter- associated UTIs (CAUTI). Acinetobacter baumanii are known to encode at least two CUP pili known to be important in CAUTI. This proposal seeks to elucidate: i) the molecular dynamics of adhesin conformational equilibriums that govern host-pathogen interactions; ii) structure-function correlates of UPEC CUP adhesins with unknown functions; and iii) structure-function correlates of Acinetobacter baumanii CUP adhesins critical in CAUTIs. This proposal will enhance the understanding of the mechanism of action of host-pathogen interactions and elucidate opportunities to develop much needed antibiotic-sparing therapeutics that block the ability of these uropathogens to colonize/infect host tissues such as mannosides for which a candidate has been chosen for clinical trials.
Urinary tract infections (UTIs) and catheter associated UTIs are common and increasingly antibiotic resistant. Thus, a high resolution understanding of the mechanisms of host-pathogen interactions is needed to spawn the development of new antibiotic-sparing therapeutics that interrupt interactions necessary for virulence. Thus, we will elucidate structure-function correlates of a repertoire of chaperone usher pathway (CUP) pilus adhesins encoded by the most common uropathogen, uropathogenic E. coli, and CUP adhesins encoded by Acinetobacter baumanii, a frequently multidrug pathogen that causes increasing numbers of opportunistic infections. The receptor specificity, structures and dynamics of CUP adhesins will transform the field by providing a new conceptual framework in microbial pathogenesis focused on events critical to host colonization and uncovering new therapeutic strategies to treat or prevent disease.
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