Shamseddine Lama, Roblin Clarisse, Veyrier Iris, Basset Christian, De Macedo Lisa, Boyeldieu Anne, Maresca Marc, Nicoletti Cendrine, Brasseur Gaël, Kieffer-Jaquinod Sylvie, Courvoisier-Dezord Élise, Amouric Agnès, Carpentier Philippe, Campo Nathalie, Bergé Mathieu, Polard Patrice, Perrier Josette, Duarte Victor, Lafond Mickael
University Grenoble Alpes, CNRS UMR5249, CEA, IRIG, Laboratoire Chimie et Biologie des Métaux, 38054 Grenoble, France.
Aix Marseille University, CNRS, Centrale Marseille, iSm2, 13013 Marseille, France.
iScience. 2023 Aug 6;26(9):107563. doi: 10.1016/j.isci.2023.107563. eCollection 2023 Sep 15.
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 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.
在发现对抗生素耐药性的新分子成为公共卫生问题的情况下，核糖体合成及翻译后修饰的肽构成了一种有前景的替代方案。在此背景下，革兰氏阳性人类肠道共生菌E1产生五种硫肽，即瘤胃球菌素C1至C5（RumC1 - C5），它们与两种自由基S - 腺苷甲硫氨酸成熟酶共表达。已证明RumC1对多种耐多药革兰氏阳性临床分离株有效。在此，在调整生物合成方案以获得四种成熟的RumC2 - 5后，我们接着评估它们的抗菌活性。首先确定两种成熟酶均表现出底物耐受性，然后我们观察到五种异构体之间抗菌功效存在差异。我们确定所有RumC对人类都是安全的且具有有趣的多功能性。虽然未观察到五种RumC之间存在协同作用，但我们发现它们与靶向细胞壁的传统抗生素存在协同作用。最后，我们确定了RumC异构体抗菌活性的关键残基。
