Design And Development Of Quinoline-Based Biofilm Inhibitors Against V. Cholerae

Bacterial biofilms are composed of surface associated communities of bacteria encased in a protective extracellular matrix. Bacterial biofilms are a major medical issue because of their increased levels of resistance to traditional antibiotics. It is believed that antibiotic resistant bacteria cost up to $20 billion per year. This problem is not just financial, because the NIH estimates that about 75% of pathogenic microbial infections are biofilm mediated. For this reason, our laboratory has begun a program to discover biofilm inhibitors/molecular probes that will allow us to study biofilm progression and physiology, as well as providing new avenues for therapeutic intervention. Initial studies began with the devlopment of a high-throughput screen for Vibrio cholerae biofilm inhibitors. Subsequent screening of compounds from the National Cancer Institute identified a suite of lead compounds. An efficient and divergent synthesis of compounds with this general scaffold were prepared for medicinal chemistry development. The lead compound synthesis begins from 2, 4 Dibromoquinoline via an organomagnesium reagent being formed at carbon 4, which subsequently adds into an aldehyde. Next, carbon carbon bond formation at carbon 2 was formed with a boronic acid via a Suzuki cross coupling. The completed set of compounds were then subjected to our high-throughput image based biofilm screen. With this set of compounds and data we plan on performing co-dosing studies with antibiotics, as well as working with collaborators to determine the molecular targets of this compound series.