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 that target a previously unexplored mechanism: trans-translation. This rescue process of bacterial ribosomes that have become stalled during protein synthesis is essential for bacteria survival and is specific to prokaryotes, making it an ideal and selective target. More specifically, our strategy is based on the C-terminal tail of the SmpB protein, a key player in this recognition process. By designing peptides that mimic this tail, we seek to block trans-translation, thereby offering a therapeutic alternative potentially free of resistance mechanisms. This work demonstrates that a peptide comprising the last 29 amino acids of the C-terminal tail of SmpB selectively and effectively inhibits trans-translation in vitro in E. coli. Its mechanism of action, which involves competition with the native SmpB protein, has been validated by cryo-EM. This candidate was optimised by developing a shortened 24-amino acid version, which was further improved through modifications to the sequence and secondary structure. A second phase of midifications enabled the identification of a 17 amino-acid peptide with limited loss of 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, [email protected]