The rise of antibiotic resistance has driven the search for alternative approaches to tackle infection, including targeting non-essential virulence processes. Anti-virulence therapies are non-fatal to bacteria and are less likely to give rise to resistance due to decreased selection pressure. Biofilms are an attractive virulence factor target as bacteria in biofilms are more resistant to antibiotics and thus more difficult to treat. Here, potential inhibitors of biofilm-related virulence are synthesized and evaluated. During the process of biofilm formation, bacteria capitalize on lectin-carbohydrate interactions with their host and quorum sensing communication. Various strains of Escherichia coli (E. coli) express carbohydrate-binding adhesins that lead to colonization of mammalian urinary and digestive tracts. One of these lectins, F17G (and the almost identical GafD), is present in enterotoxigenic E. coli strains and recognizes and binds to N-acetylglucosamine (GlcNAc) on host glycans. Preliminary docking and virtual screening have confirmed that longer hydrophobic chains or aromatic groups at either the anomeric position or the amide position of GlcNAc may improve binding. We have synthesized a small library of potential inhibitors, and these ligands are being tested for competitive activity in ELISA-like assays. Quorum sensing is another important factor in bacterial pathogenesis and virulence. LuxS is a widely conserved enzyme that synthesizes a common small quorum sensing signal, autoinducer-2 (AI-2). The LuxS enzyme has a nucleophilic cysteine in the active site, making it prone to covalent inhibition. In this effort, electrophiles with pendant alkynes have been synthesized to probe the reactivity and selectivity of the LuxS cysteines and to develop a fluorescence-based assay to screen potential inhibitors.

Targeting biofilms with inhibitors of lectin-mediated adhesion and quorum sensing

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