Partnership : It involves a complementary consortium (Pr F.-H. Porée, N. Quéméré & Dr C. Gadais = Chemists - partner 1-, and Pr. Reynald Gillet, Dr. Olivier Delalande & Dr. Emmanuel Giudice, IGDR UMR 6290 = Biologist and modelisation - partner 2).
Hypothesis, object and methodology: Based on high resolution Cryo-EM technology, elucidation of the interactions between tmRNA, SmpB and the stalled ribosome by partner 2 has unveiled the importance of the SmpB C-terminal tail in the trans-translation process. Proof-of-concept of this hypothesis was validated in E. coli for which trans-translation inhibition was demonstrated using its SmpB-29-residues C-terminal domain. Since inhibition of this pathway could ultimately lead to bacterial death, SmpB C-terminal tail constitutes a promising starting point for the design of new series of potent antibiotics displaying a unique mechanism of action. In this project, we plan to work on peptides mimicking the SmpB C-terminal tails of ESKAPE pathogens as decoys for trans-translation inhibition and their antibiotic applications: more precisely, their synergistic effect with putative ribosome-targeting compounds will be investigated.
This project benefits from the “Défi Volet 2 interdisciplinaire Université de Rennes” Grant (2022-2023) and a doctoral fellowship “Politique établissement” (CDPE 2023-2026) was also granted. In the frame of this project, the team also benefited from several financial supports (AES Rennes Métropole and Fondation Langlois) and the support of Olgram (a start-up we are collaborating with - https://www.olgram.com/) and CNRS to acquire a new automated peptide synthesizer (Liberty blue 2.0, delivery in summer 2023).