Mechanistic and functional aspects of the Ruminococcin C sactipeptide isoforms

In a scenario where the discovery of new molecules to fight antibiotic resistance is a public health concern, ribosomally synthesized and post-translationally modified peptides constitute a promising alternative. In this context, the Gram-positive human gut symbiont Ruminococcus gnavus E1 produces five sactipeptides, Ruminococcins C1 to C5 (RumC1-C5), co-expressed with two radical SAM maturases. RumC1 has been shown to be effective against various multidrug resistant Gram-positives clinical isolates. Here, after adapting the biosynthesis protocol to obtain the four mature RumC2-5 we then evaluate their antibacterial activities. Establishing first that both maturases exhibit substrate tolerance, we then observed a variation in the antibacterial efficacy between the five isoforms. We established that all RumCs are safe for humans with interesting multifunctionalities. While no synergies where observed for the five RumCs, we found a synergistic action with conventional antibiotics targeting the cell wall. Finally, we identified crucial residues for antibacterial activity of RumC isoforms.

Automated summary

In the context where discovering new molecules to combat antibiotic resistance is important for public health, ribosomally synthesized and post-translationally modified peptides, known as sactipeptides, show promise as an alternative. In this study, the gut symbiont Ruminococcus gnavus E1 was found to produce five sactipeptides, named Ruminococcins C1 to C5 (RumC1-C5), along with two maturases. The antibacterial activities of the mature forms of RumC2-5 were evaluated and variations in efficacy and synergy with conventional antibiotics were observed.