Drug DISCOVERY Specific Seminar – James Janetka, PhD

Pharmaceutical Sciences Seminar Series

Antivirulence Drugs as an Alternate Strategy to Antibiotics

(Drug DISCOVERY Specific Seminar)

• James Janetka, PhD
• Washington University

The global rise in multi-drug resistant bacteria underscores the urgent need for new antibiotic-sparing therapeutics. Pili are long chain proteinaceous structures on the surface of Gram-negative bacteria and tipped with bacterial adhesins which are known virulence factors. These adhesins contain a lectin domain which binds specifically to carbohydrate receptors on host cells. Binding through these lectin domains leads to persistence of Uropathogenic Escherichia coli (UPEC) in urinary tract infections (UTI), one of the most common infections worldwide. Examples of chaperone usher pathway (CUP) pili in UPEC include the mannose-binding FimH, and the galactose-binding PapG and FmlH lectins. Here, we describe the rational design of small molecule glycomimetics as high affinity ligands which act as molecular decoys and block FimH and FmlH from adhering to host cells. Through an interdisciplinary approach that blended medicinal chemistry, X-ray crystallography, virtual and biochemical screening, bio-layer interferometry, immunofluorescence, and mouse models of UTI, we have developed orally bioavailable biaryl mannosides and galactosides that bind FimH and FmlH with nanomolar affinity and prevent bacterial attachment and biofilm formation. There is overwhelming therapeutic value of leveraging a deep understanding of structure-function relationships of bacterial adhesins for the development of anti-virulence strategies that disrupt host-pathogen interactions for treatment of infectious disease. The shape of the extended binding surface surrounding the sugar pocket (e.g. tyrosine gate in FimH), which is determined by its carbohydrate receptor binding epitope, can be effectively mimicked with a monosaccharide bearing an appropriately substituted biaryl ring aglycone. This antibiotic-sparing approach is effective in treating antibiotic-resistant forms of bacteria and has high potential to significantly reduce or even eliminate resistant microbes. This strategy will be useful in expediting the development of future glycomimetic lectin antagonists as novel anti-infective agents.

Hosted by Jiaoyang Jiang