Objectives
Research Programme
Peptidoglycan is a polymer which is completely specific to the bacterial world and the enzymes which contribute to its biosynthesis have no counterparts in the eukaryotic organisms. This explains the success of penicillins and related b-lactam compounds which take advantage of both factors: the extracellular localisation of the target and the uniqueness of the prokaryotic organisms.
The present project targets the intra- and extracellular steps of peptidoglycan biosynthesis and the related process of cell morphogenesis. Peptidoglycan is formed by linear glycan chains composed of alternating N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (GlcNAc) residues cross-linked by short peptides. It completely surrounds the cell and determines its shape. Its biosynthesis can be divided into three steps.
- Intracellular steps resulting in the synthesis of UDP-MurNAc-peptide and UDP-GlcNAc. The structure of the peptides is unique to the bacterial world as it contains non-proteinaceous amino acids as well as D-amino acids.
- Transfer of the two precursors onto a phosphorylated C55-isoprenoid, a membrane soluble carrier. Amino acids can be added to the peptide at this stage. The carrier-linked disaccharide-peptide (Lipid II) is then transferred to the external face of the cytoplasmic membrane.
- Polymerisation of the saccharide chains by a transglycosylation reaction and cross-linking of the so-formed linear polymers by a transpeptidation reaction. Both activities are carried out by the same proteins, the class A penicillin-binding proteins (PBPs). Class B PBPs only catalyse the transpeptidation reaction, but interact with other proteins to regulate and perform the cell division process. The transpeptidase activity of the PBPs is the target of b-lactam antibiotics and the appearance of PBPs of very low affinity for b-lactams in Staphylococcus aureus, Streptococcus pneumoniae and Enterococci is a worrying phenomenon.
The project is financed by the European Commission under The Sixth Research Framework Programme and coordinated by the University of Liege through The Center for Protein Engineering.