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ANR funded project

Blanc - SVSE 8 - Biochimie, biologie moléculaire et structurale (Blanc SVSE 8) 2013
Projet BACSCREEN

Assembly and structure of macromolecular complexes involved in bacterial cell wall biosynthesis

The bacterial cell wall is a complex three-dimensional structure that protects the cell from environmental stress and ensures its shape. It also plays a key role during the processes of cell division and bacterial cell wall elongation. The biosynthesis of its main building block, the peptidoglycan, involves the coordination of activities of proteins present in both cytoplasmic and periplasmic compartments, some of which also interact with the bacterial cytoskeleton. Although targeting the peptidoglycan biosynthetic pathway with ß-lactam antibiotics has been a highly successful strategy to combat bacterial infections for over eighty years, antibiotic resistant strains have been reported worldwide. Notably, the sheer complexity of the cell wall formation process has created a significant challenge for the development of novel antibacterials as well as for the study of the macromolecular interactions that regulate peptidoglycan biosynthesis.

In the BACSCREEN project, we will structurally and functionally characterize macromolecular complexes involved in both cytoplasmic and periplasmic phases of peptidoglycan biosynthesis. We will tackle the study of a cytoplasmic complex formed by Mur synthetases, proposed to act in “channelling” of peptidoglycan building blocks towards the membrane, as well as PBP assemblies, involved in the two last enzymatic reactions required for peptidoglycan biosynthesis. We will accomplish these goals through the employment of a combination of X-ray crystallography, small angle scattering (SAXS), electron microscopy, and genetic and microbiological methodologies. In addition, by using a time-resolved fluorescence assay that is already available to us through a collaboration with Hybrigenics and that detects interactions between PBP and its periplasmic partners, we will screen chemical libraries in the search for inhibitors of such interactions; in addition, chimeric molecules will also be developed. The availability of preliminary results obtained through the collaboration between the two partners involved, including a fluorescence assay already proven to identify interactions within PBP assemblies, indicates that the work proposed here will succeed in revealing key aspects of peptidoglycan assembly machineries that will be important not only for the drug development field but also for the understanding of general mechanisms of bacterial cell wall synthesis and macromolecular complex formation.

Partners

CEA/DSV/IBS commissariat à l'énergie atomique et aux énergies alternatives

IP Institut Pasteur-UBGPB

ANR grant: 400 000 euros
Beginning and duration: novembre 2013 - 48 mois

 

ANR Programme: Blanc - SVSE 8 - Biochimie, biologie moléculaire et structurale (Blanc SVSE 8) 2013

Project ID: ANR-13-BSV8-0015

Project coordinator:
Madame Andrea DESSEN (commissariat à l'énergie atomique et aux énergies alternatives)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.