The main goal of this project is to use an integrative approach to develop novel antimicrobial molecules targeting ribosomal trans-translation in multi-resistant pathogenic bacteria. Trans-translation is performed by the hybrid transfer-messenger RNA (tmRNA) and its protein partner SmpB. Given the absence of trans-translation in eukaryotes, the molecular components of this process are particularly attractive targets for new broad-spectrum antibiotics and/or for the enhancement of existing inhibitors of protein synthesis in humans or animals. Indeed, it is essential for either the survival or virulence of many pathogenic bacteria. In cases where the deletion is not lethal, it induces hypersensitive phenotypes thus making antibiotics more efficient. By using a combination of biochemical, biophysical, structural and microbiological approaches we expect to discover a new class of compounds inhibiting trans-translation with specificity in pathogenic bacteria.