Helene Barreteau, Libera Latino, Dimitri Cherier, Delphine Patin, Didier Blanot, Thierry Touze and Dominique Mengin-Lecreulx
University of Paris-Saclay, France
Posters & Accepted Abstracts: J Infec Dis Treat
Colicins are plasmid-encoded bacteriocins produced by some Escherichia coli strains in order to kill competitors belonging to the same or related species. All known colicins share a same structural organization in three domains, each of them being devoted to a specific function: translocation through the outer membrane, binding to a specific outer membrane receptor and toxicity, from N to C termini, respectively (Cascalès et al., 2007). Among colicins, colicin M (ColM) is the smallest colicin known to date and the only one known to interfere with peptidoglycan biosynthesis. It targets and cleaves the peptidoglycan lipid II intermediate at the periplasmic face of the inner membrane by exhibiting a phosphodiesterase activity leading to the formation of undecaprenol and 1-pyrophospho-MurNAc-(pentapeptide)- GlcNAc (El Ghachi et al., 2006). These two products cannot be used or recycled for peptidoglycan biosynthesis, leading to cell lysis. During last years, several homologues of ColM produced by various bacteria such as Pseudomonas (Barreteau et al., 2009), Burkholderia (Ghequire and De Mot, 2015) and Pectobacterium (Grinter et al., 2012, 2014) were identified and characterized. These ColM-like proteins exhibit the same mode of action as ColM and displayed cytotoxic activity towards a limited number of bacterial species. Accordingly, no crossed cytotoxic activity has been demonstrated (Barreteau et al., 2009; Chérier et al., 2016), presumably due to the high specificity of reception and translocation machineries. Thus, reaching the lipid II target is clearly the crucial and limiting step to be considered in a perspective of exploitation of these colicin family members as tomorrow’s antibiotics. We recently showed that the pectocin M1 (PcaM1, produced by P. carotovorum) and some of its variants were able to kill E. coli cells once addressed to the periplasm of this species using appropriate pASK vectors (Chérier et al., 2016). In these conditions, PcaM1 and its isolated catalytic domain were effectively able to catalyze the degradation of lipid II, leading to the arrest of peptidoglycan biosynthesis and cell lysis. To the best of our knowledge, this was the first example of a ColM-like protein capable of killing another bacterial species, without any treatment affecting cell wall integrity. This result and the fact that lipid II is an essential and specific component through the whole bacterial world make of ColM and its orthologues very interesting agents to be exploited as new antibacterial agents. We thus propose the creation of a range of chimera colicins by an engineering approach, in order to get potent antibacterial molecules able to fight, either specifically or not, against various pathogenic bacterial species. Our first goal consists in getting chimera proteins with a narrowspectrum antimicrobial activity. Our presentation will deal with our preliminary and encouraging results.
Helene Barreteau has completed her PhD in Biochemistry and Microbiology at the Université de Picardie Jules Verne (Amiens, France) and postdoctoral studies from the Université Paris-Sud (Orsay, France), CNRS (Grenoble, France) and the Muséum National d’Histoire Naturelle (Paris, France). She currently works as assistant professor in Biochemistry at the Université Paris- Sud and has published 35 papers in reputed journals.
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