The bacterial cell wall: Mobashery and the mechanics of resistance

2007 — today

The wall, drawn at last: Shahriar Mobashery's laboratory at Notre Dame took up the structure penicillin attacks. For half a century the bacterial cell wall's mesh — peptidoglycan — had resisted structural description, because fragments of it could not be isolated pure or in quantity. In a paper in the Proceedings of the National Academy of Sciences, reported by the university in January 2007, Mobashery and his team characterized the framework of peptidoglycan for the first time, by synthesizing a fragment of the wall through a thirty-seven-step procedure and reading its structure by nuclear magnetic resonance and computation — the three-dimensional image, in the university's account, that removed an obstacle slowing the design of new antibacterials, and the means to understand with unprecedented clarity how penicillin and vancomycin do their work on the wall.

The resistance work followed the structure into the enzyme that defeats the drugs. MRSA's penicillin-binding protein 2a performs the wall's cross-linking while refusing the antibiotics; in PNAS in 2013 the Notre Dame group, with Mayland Chang and Spanish collaborators, documented the protein's allosteric control — a fragment of cell wall binding sixty ångströms from the active site triggers the opening that lets the enzyme work — and showed that the newly approved antibiotic ceftaroline turns the mechanism against the bacterium, binding the allosteric site itself so that a second molecule can enter and disable the active site, a mechanism the paper's authors called unprecedented. The laboratory's own drug candidates stand in the record at the size the reviews give them: the oxadiazoles, a non-β-lactam class found by computational docking against a penicillin-binding protein, active against MRSA and vancomycin-resistant enterococcus and effective in mouse models of infection, as the field's 2016 review of the work summarizes. The American Chemical Society marked the line of work in 2008 with an Astellas USA Foundation Award to Mobashery for his contributions to understanding antibiotic resistance and the bacterial cell wall.

Sources:

1. University of Notre Dame, College of Science news (January 2007) — the PNAS characterization of the peptidoglycan framework for the first time, the thirty-seven-step synthesis of the cell-wall fragment, the team of Meroueh, Hesek, Lee and Fisher at Notre Dame with Bencze and Stemmler of Wayne State.
2. Otero et al. with Mobashery and Chang, "How Allosteric Control of Staphylococcus aureus Penicillin Binding Protein 2a Enables Methicillin Resistance and Physiological Function," Proceedings of the National Academy of Sciences (2013) — the allosteric site sixty ångströms from the active site and ceftaroline's two-molecule mechanism, as the university's and Phys.org's accounts of the paper report it.
3. Janardhanan et al., "The Oxadiazole Antibacterials," Current Opinion in Microbiology 33 (2016) — the oxadiazole class discovered by in silico docking, its activity against MRSA and vancomycin-resistant Enterococcus, and its in vivo efficacy in murine models.
4. Chemical Biology & Drug Discovery news, University of Notre Dame (22 July 2008) — Mobashery's 2008 Astellas USA Foundation Award from the American Chemical Society; the laboratory's PBP 2a work and the synthetic cephalosporins investigated with Cerexa.