CBMS Lecture Series

The bacterial cell wall is important for survival and shape, and its biosynthetic mechanism is the target of beta-lactam antibiotics. The spread of resistant strains, however, has limited the usefulness of these drugs and calls for efforts towards studies of cell wall formation that could lead to the development of innovative treatments. My group is interested in structurally and functionally characterizing protein complexes involved in both cytoplasmic and periplasmic steps of cell wall biosynthesis. The synthesis of peptidoglycan, the main component of the cell wall, starts in the cytoplasm, through sequential reactions catalyzed by Mur enzymes that have been suggested to associate into a multi-membered complex. This idea is supported by the observation that in many bacteria, mur genes are present in a single operon within the well conserved dcw cluster, and in some cases pairs of mur genes are fused to encode a single, chimeric polypeptide able to catalyze successive reactions. I will present the crystal structure of the MurE-MurF chimera from Bordetella pertussis, which reveals a head-to-tail, elongated architecture and indicates how sequential reactions could be catalyzed. In addition, I will also discuss structural details of complexes formed in the bacterial periplasm, notably between Penicillin-Binding Proteins (PBPs) and the scaffolding protein MreC, that act in partnership with Mur proteins in the cell wall biosynthesis process. These structural and functional insights shed light on the importance of studying pathways that are of critical relevance for bacterial cell survival in light of the antibiotic resistance crisis.