The unusual structure of Ruminococcin C1 antimicrobial peptide confers clinical properties

authors

• Roblin Clarisse
• Chiumento Steve
• Bornet Olivier
• Nouailler Matthieu
• Müller Christina S.
• Jeannot Katy
• Basset Christian
• Kieffer-Jaquinod Sylvie
• Couté Yohann
• Torelli Stéphane
• Le pape Laurent
• Schünemann Volker
• Olleik Hamza
• de La Villeon Bruno
• Sockeel Philippe
• Di Pasquale Eric
• Nicoletti Cendrine
• Vidal Nicolas
• Poljak Leonora
• Iranzo Olga
• Giardina Thierry
• Fons Michel
• Devillard Estelle
• Polard Patrice
• Maresca Marc
• Perrier Josette
• Atta Mohamed
• Guerlesquin Francoise
• Lafond Mickaël
• Duarte Victor

keywords

• RiPPs
• Ruminococcin C
• Sactipeptide
• Gut microbiome
• Antibiotic
• Radical SAM enzyme
• RiPP
• Ruminococcus gnavus

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 with reversed stereochemistry introduced posttranslationally 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.

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