TRANSPEPTID · Developing new antibiotic peptides targeting ESKAPE bacterial trans- translation

Antimicrobial resistance (AMR) poses a major threat to human health around the world. The AMR crisis has emerged as one of the leading public health threats of the 21st century. This global crisis is due to the fact that bacteria share and increasingly develop new resistance mechanisms as a consequence of the misuse of antibiotics, as well as a lack of new drug development. To combat this crisis, we need new classes of antibiotics, and most importantly, against new targets. It is therefore crucial to identify new molecular processes that can be targeted. Ideally, these should be: i) conserved among all pathogenic ESKAPE bacteria; ii) indispensable to bacterial survival or at least its fitness; iii) sufficiently variable that different species can be distinguished from each other; iv) absent in eukaryotes; v) not targeted by current antibiotics; vi) unrelated to existing AMR mechanisms; and finally, vii) reproducible in non- hazardous in vitro experiments. In this quest, trans-translation appears to be a perfect candidate. Development of new antibiotics that target trans-translation from multidrug resistant ESKAPE pathogens will be addressed in this project (TRANSPEPTID). We will use engineer antimicrobial peptides based on the C- terminal tails of SmpB proteins from ESPAKE pathogens with the propose to compete with endogenous SmpB, and in turn to inhibit trans-translation. The project is organized in three main objectives that will constitute three major breakthroughs in the field: (OB1) Optimization and characterization of designed peptides in ESKAPE pathogens, (OB2) Biophysical analysis of selected peptides in target ESKAPE pathogens, and (OB3) Determination of the high- resolution structures of the complexes between the peptides and their molecular targets by cryo-EM. Since TRANSPEPTID is a multidisciplinay project that embraces both fundamental and applied science, it will contribute significantly to strength the research and training profile of the researcher