RiPPing through pathogenic bacteria and protein-protein interactions

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a rapidly expanding class of chemically and structurally diverse bacterial natural products. Many exhibit therapeutically important biological activities, such as antibiotic, antifungal, insecticidal, immunomodulating and anti-cancer activities. The relaxed substrate specificity of RIPP biosynthetic enzymes, together with the increasing availability of methods to efficiently introduce multiple site-directed mutations, opens the door to generating large libraries of RiPP variants that can be screened for improved pharmaceutical properties. Sactipeptides are macrocyclic RiPPs featuring a unique hairpin-like structure that provides a promising scaffold for the development of novel therapeutics. By combining the promiscuity of RiPP biosynthesis with a droplet-based microfluidic screening platform, I aim to push the boundaries regarding RiPP engineering for therapeutic applications. In this project, I will construct and screen unique sactipeptide libraries for novel derivatives with activity against oncogenic gut pathogens as well as selective protein-protein interaction inhibitors that can inactivate the type VI secretion system in Vibrio cholera.