Catalysing basic research: Peptidoglycan biosynthesis - still attractive after all this time Christopher G. Dowson, David I. Roper, Adrian J. Lloyd.

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Presentation transcript:

Catalysing basic research: Peptidoglycan biosynthesis - still attractive after all this time Christopher G. Dowson, David I. Roper, Adrian J. Lloyd

The bacterial cell wall - peptidoglycan A scaffold -turgor pressure /osmotic shock An anchoring point -antigens and virulence factors Peptidoglycan precursors/fragments -stimulate the innate immune system MurNac = N-acetyl muramic acid GlcNac = N-acetyl glucosamine MurNac GlcNac G+ve G-ve

CytoplasmicSynthesis of a UDP-Sugar Pentapeptide Membrane-bound (intracellular)Attachment to a lipid carrier, addition of crosslinking amino acids and an extra carbohydrate ExtracellularCrosslinking of pentapeptide and carbohydrate to yield final polymer Peptidoglycan biosynthesis – The essentials

Peptidoglycan architecture – New Perspectives MurNac GlcNac 1 μm 100nmP Inside Outside

Peptidoglycan synthesis is Unique to and essential for bacterial cell viability The peptidoglycan synthesising enzymes are therefore good targets for antibiotics (both natural and man-made) However, bacteria can go to some lengths to develop resistance

New understanding- It’s complex By: den Blaauwen et al. (2008) FEMS Microbiol Rev: 32(2), 321–44

New uncharacterised domains within penicillin binding proteins (PBPs) Class A Class B Class C C-terminal transpeptidase N-terminal transglycosylase High molecular mass C-terminal transpeptidase Undetermined N-terminal function High molecular mass Monofunctio- nal carboxypepti- dases Low molecular mass By: Sauvage E, Terrak M, Ayala JA, Charlier P. FEMS 2008;32:234–258.

97,000 66,000 45,000 31,000 20,000 14,000 BADCFE MrMr MrMr 97,000 66,000 45,000 31,000 20,000 14,000 New reagents - Re-constitution of peptidoglycan precursor biosynthesis in vitro Pseudomonas aeruginosa MurA-F Micrococcus flavus membranes M. Flavus MraY and MurG Enzymatic Synthesis of every peptidoglycan precursor including Lipid II

UDP GlcNAc UDP MurNAc UDP MurNAc-A UDP MurNAc-AE UDP MurNAc-AEK/meso-DAP UDP MurNAc-AEKAA Lipid I Lipid II MurA MurB MurC MurD MurE MurF Mray UDP enol-pyruvoyl- GlcNAc MurG Lipid II-Ala MurM D-Ala-D-Ala D-Ala LL-DAP DDL meso- DAP Lipid II-Ala-Ala MurN DAPF Lys New assays

MurNac GlcNac Lipid II Harnessing the biosynthesis of peptidoglycan intermediates in vitro

CanUK Team in Novel antibacterial targets, assays, probes and opportunities in bacterial cell wall biogenesis U. Guelph, McMaster, Laval, British Columbia U. Warwick, Birmingham, Newcastle,Sheffield fesci/people/droper/bacwan/ synthesis facility Academic Industry Partnership New collaboration models

Growth, Protein Structure, Assays for drug discovery 30k 24k 60k