Peptides Synthesis

Development of new peptide-based antimicrobial compounds targeting trans-translation in multiresistant bacteria.

Team : Charlène Gadais, Nicolas Quéméré, François-Hugues Porée, Doctorant.e (PhD CDPE 2023-2026)

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).

This emerging project is devoted to the identification of a potent new class of antibiotics with an original and unique mechanism of action. 
Scientific background: Despite the increasing number of studies proving the worldwide antibio-resistance spreading, Big Pharma interests for new antibiotic drugs are minimal since economic stakes are high and return on investment low. In particular, the ESKAPE group of bacteria represents a serious concern for which the WHO urges the scientific community to find new therapeutic solutions. In this context, we would take advantage of the identification of a unique bacterial process to develop a new class of antibiotics. Errors in ribosomal protein synthesis are inevitable events that could lead to cell death. To prevent such fatal consequences, bacteria activate a rescue system called trans-translation that permits resuming translation and destroying faulty proteins. In this process, a small protein called SmpB, recognizes stalled ribosomes by inserting its C-terminal tail in the vacant mRNA path of stalled ribosomes. This way it allows the correct positioning of its partner, transfer-messenger (tmRNA), into the ribosomal A-site (Figure 1). The nascent faulty peptide is tagged for degradation, the problematic mRNA is destroyed and the ribosome is recycled for a new round of translation. Exclusive to prokaryotic cells, this “rescue system” constitutes a highly valuable target for the development of new classes of antibiotics with potentially broad-spectrum of activity, and limited side-effects on host cells.

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 - and CNRS to acquire a new automated peptide synthesizer (Liberty blue 2.0, delivery in summer 2023).