Research

Urinary Tract InfectionUPEC genomics/geneticsChaperone/Usher Pathway PiliEnterococcal pathogenesis/catheter-associated UTIBacterial amyloid (Curli) biogenesisBacterial Community Interactions (Biofilms and Microbiome)Drug and Vaccine Development

Drug and Vaccine Development

Pili and Curli Inhibitors

Pili and Curli Inhibitors

With dire predictions of antibiotic resistance reaching a tipping point, it is imperative that we develop novel, antibiotic-sparing medicines to avoid a future in which we face increasing deaths due to previously treatable common infections. We are focused on this mission by elucidating potential therapeutic targets in critical host-pathogen interactions for one of the most common infections in the United States, urinary tract infection (UTI), which has a significant economic toll on this country’s health system. UTIs are one of the most common afflictions of females with over 11 million women suffering 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 quality of life through pain, discomfort, disruption of daily activities, and increased healthcare costs. This problem is being exacerbated by the rapid spread of antimicrobial resistance among uropathogenic Escherichia coli (UPEC), the cause of over 80% of UTIs. Patients suffering from a symptomatic UTI are commonly treated with broad-spectrum antibiotics. However, rates of antibiotic resistance are confounding UTI treatment for millions of women annually. Importantly, 25% of all adult sepsis cases can be traced back to the urinary tract. Improved treatments for UTI will therefore greatly reduce the incidence of sepsis, which increasingly involves multidrug resistant bacteria and is associated with an overall mortality rate of 20-40%. Thus, UTIs and UPEC are a “canary in the coal mine,” warning us of the coming antibiotic resistance crisis and the need for new antibiotic-sparing therapeutic strategies that can be developed by a deeper understanding of host-pathogen interactions

Mannoside treatment rationale

Mannoside treatment rationale

We are focused on developing antibiotic-sparing therapeutics that capitalize on our knowledge of adhesins critical in UTIs. We target these adhesins to block colonization, and biofilm formation by UPEC, Klebsiella, Acinetobacter and Enterococcus during UTIs and/or CAUTIs. The advantage of this approach is that it is efficacious against both antibiotic-resistant and antibiotic-sensitive pathogens. Further, targeting adhesins promises to be particularly effective in infections of mucosal surfaces where fluid flow across the tissue surface is part of the host defense to expel pathogens from the host. The ability of pathogens to resist being removed from the host by expressing adhesins that bind to host tissues is thus critical for colonization and the ability to cause infections. Targeting critical extracellular adhesive interactions will make development of resistance by the pathogen less likely, since the therapeutic will be recalcitrant to intracellular mechanisms of resistance such as: i) enzymes that degrade the antibiotic; ii) pumps that expel the antibiotic; and iii) mutations that prevent the entry or action of the antibiotic. Further, mutations in the binding pocket of targeted adhesins to prevent binding of the therapeutic would likely also destroy adhesin function rendering the pathogen non-virulent.

Gene expression in response to pilicides

Gene expression in response to pilicides

We have had considerable success targeting adhesins, both for rational design of receptor analogues and for vaccine development. We, in collaboration with Dr. Jim Janetka, have designed compounds called mannosides that neutralize the function of the FimH adhesin that tips type 1 pili, which is required for UPEC to cause UTI. Orally bioavailable mannosides are highly efficacious in treating and preventing UTI in pre-clinical models, independent of the antibiotic resistance profiles of the pathogen. This has led to the founding of Fimbrion Therapeutics, which has further developed mannosides and a mannoside has now been selected for clinical trials in humans in collaboration with Glaxo Smith-Kline. Further, validation of FimH as a therapeutic target led to a phase 1a/1b FimH-based vaccine clinical trial that was completed successfully leading to its allowance by the FDA for compassionate use in individuals suffering from rUTI who no longer respond to standard of care, including last-line carbapenem agents. In addition, in collaboration with Dr. Fredrik Almqvist’s group, we have developed novel inhibitors of pili biogenesis, called pilicides, which were shown to inhibit UPEC biofilm formation in vitro and decrease type 1 pilus formation.

Collaborators: Fredrik Almqvist, Jim Janetka, Sequoia Sciences, Fimbrion Therapeutics.

Top