L. Le Corre, R. Ben-Othman, M. Oliver, M. Fer, S. Calvet-Vitale and Christine Gravier-Pelletier
Université Paris Descartes, Sorbonne Paris Cité, CICB-Paris, UMR CNRS 8601, LCBPT 45 Rue Des Saints Pères, 75270 Paris 06,
Infectious diseases are one of the most important causes of human death in the world and the emergence of nosocomial infections involving Multi Drug Resistant bacterial strains has become a severe health problem classified by the WHO among the top 10 research priorities. This is why new bacterial targets are looked for to develop novel antibiotics. As an essential feature of bacterial cell wall, peptidoglycan and its biosynthesis remain a fertile ground to explore. The enzymes involved in this biosynthesis have been demonstrated ubiquitous and essential for bacterial viability and represent crucial targets towards new antimicrobials.
The presentation will focus on the synthesis of new inhibitors of the transferase MraY which catalyzes the first membrane-associated step of peptidoglycan biosynthesis and is currently the target of no antibiotics in clinical use. The diversity-oriented synthesis of several families of inhibitors, notably through multi-component approaches, will be presented. Results of in vitro and in cellulo (collaboration with Dr A. Amoroso, Pr B. Joris, CIP Liège) biological evaluations of the synthesized inhibitors will be discussed and rationalized by molecular modelling studies.
Keywords: Nucleoside antibiotics, CuAAC, Ugi-Azide, biological evaluation.