The unusual structure of Ruminococcin C1 antimicrobial peptide confers clinical properties
Clarisse Roblin, Steve Chiumento, Olivier Bornet, Matthieu Nouailler, Christina S. Müller, Katy Jeannot, Christian Basset, Sylvie Kieffer‐Jaquinod, Yohann Couté, Stéphane Torelli, Laurent Le Pape, Volker Schünemann, Hamza Olleik, Bruno de La Villéon, Philippe Sockeel, Eric Di Pasquale, Cendrine Nicoletti, Nicolas Vidal, Leonora Poljak, Olga Iranzo, Thierry Giardina, Michel Fons, Estelle Devillard, Patrice Polard, Marc Maresca, Josette Perrier, Mohamed Atta, Françoise Guerlesquin, Mickaël Lafond, Victor Duarte
Abstract
The emergence of superbugs developing resistance to antibiotics and the resurgence of microbial infections have led scientists to start an antimicrobial arms race. In this context, we have previously identified an active RiPP, the Ruminococcin C1, naturally produced by Ruminococcus gnavus E1, a symbiont of the healthy human intestinal microbiota. This RiPP, subclassified as a sactipeptide, requires the host digestive system to become active against pathogenic Clostridia and multidrug-resistant strains. Here, we report its unique compact structure on the basis of four intramolecular thioether bridges introduced post-translationally by a specific radical-SAM sactisynthase. This structure confers to the Ruminococcin C1 important clinical properties including stability to digestive conditions and physicochemical treatments, a higher affinity for bacteria than simulated intestinal epithelium, a valuable activity at therapeutic doses on a range of clinical pathogens, mediated by energy resources disruption, and finally safety for human gut tissues.