The enterococcal cytolysin: Action mechanism and anti-virulence strategies
Ryan Moreira
Department of Chemistry, Howard Hughs Medical Research Institute
University of Illinois
Thursday, January 9, 2025
1:30 p.m.
In-person: C2-361
Abstract: The enterococcal cytolysin is a two-component ribosomally synthesized and post-translationally modified peptide (RiPPs) that is produced by virulent strains of Enterococcus faecalis which has nanomolar activity against Gram-positive bacteria and mammalian cells. Cytolysin-producing (C+) E. faecalis typically resides in the gut microbiome where it serves a commensal role, but recent studies have correlated the presence of cytolysin produced by C+ E. faecalis with negative clinical outcomes in patients diagnosed with alcoholic hepatitis. To combat cytolysin virulence, a two-pronged approach was taken that focused on understanding the bioactivity of this natural product and developing small molecule inhibitors of cytolysin maturation. In the first part of this seminar, evidence is provided for the oligomerization of cytolysin into toroidal nanostructures in aqueous solution and it is proposed that these structures are central to its mechanism of action against bacteria and mammalian cells. In the second part of this seminar, knowledge of the biosynthesis of cytolysin was used to develop non-toxic inhibitors of cytolysin maturation that attenuate cytolysin production in wild-type C+ E. faecalis. Together, these studies provide a comprehensive understanding of cytolysin virulence and lay the groundwork for in-vivo studies that can better elucidate the link between this natural product and human health.