Flore Miomandre PhD defense

Organic Chemistry & Interfaces (COrInt) team Abstract In light of the urgent threat posed by antibiotic resistance, this PhD project aims to develop new antibacterial peptides targeting an alternative mechanism: trans-translation. This process rescues bacterial ribosomes that have become stalled during protein synthesis and plays a crucial role in bacterial survival. Its specificity to prokaryotes makes it a particularly attractive target for the development of selective antibacterial agents. More specifically, our strategy focuses on a specific region of the SmpB protein, a key player in trans-translation. By designing peptides that mimic this region, we seek to interfere with trans-translation, thereby offering a promising alternative therapeutic strategy. This work demonstrates that a peptide derived from SmpB selectively and effectively inhibits trans-translation in vitro in E. coli. Its mechanism of action, involving competition with the native SmpB protein, has been investigated using cryo-EM. Structure–activity relationship studies subsequently guided the molecular optimisation of this initial candidate, leading to the identification of a promising antibacterial lead with optimised molecular features, including peptide length, while retaining substantial biological activity. Jury Olga IRANZO, CNRS Research Director, iSm2 (Marseille) / Reviewer Éric ENNIFAR, CNRS Research Director, IBMC (Strasbourg) / Reviewer Céline LANDON, CNRS Research Director, CBM (Orléans) / Examiner Guillaume COMPAIN, Associate Professor, IECB (Bordeaux) / Examiner François-Hugues PORÉE, Professor, ISCR (Rennes) / PhD Co-director Reynald GILLET, Professor, IGDR (Rennes) / PhD Co-director Charlène GADAIS, Associate Professor, ISCR (Rennes) / Supervisor Contact Flore Miomandre, flore.miomandre@univ-rennes.fr