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This work was funded by the Medical Research Council (MR/N002679/1; MR/K015753/1), the UKRI Strategic Priorities Fund (EP/T002778/1), and the Wellcome Trust (212197/Z/19/Z). L.L. thanks The Florey Institute for her Ph.D. studentship. We gratefully acknowledge the Wolfson Light Microscopy facility for their support and assistance in this work. We thank Diamond Light Source for access to the beamline I24 (mx18598) and Arnaud Basle for data collection, help with figure generation, and support. We are grateful to Joshua Sutton, Grace Pidwill, Victoria Lund, Laia PasquinaLemonche, and Chris Hill for help and advice. For the purpose of open access, the authors have applied a CC BY public copyright license to any author accepted manuscript version arising from this submission.

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Penicillin-Binding Protein 1 (PBP1) of Staphylococcus aureus Has Multiple Essential Functions in Cell Division

Publicated to:mBio. 13 (4): e0066922- - 2022-06-15 13(4), DOI: 10.1128/mbio.00669-22

Authors: Wacnik, Katarzyna; Rao, Vincenzo A.; Chen, Xinyue; Lafage, Lucia; Pazos, Manuel; Booth, Simon; Vollmer, Waldemar; Hobbs, Jamie K.; Lewis, Richard J.; Foster, Simon J.;

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Abstract

Bacterial cell wall peptidoglycan is essential, and its synthesis is the target of clinically important antibiotics such as beta-lactams. beta-lactams target penicillin-binding proteins (PBPs) that assemble new peptidoglycan from its building blocks. The human pathogen Staphylococcus aureus only has two essential PBPs that can carry out all the functions necessary for growth and division.Bacterial cell division is a complex process requiring the coordination of multiple components to allow the appropriate spatial and temporal control of septum formation and cell scission. Peptidoglycan (PG) is the major structural component of the septum, and our recent studies in the human pathogen Staphylococcus aureus have revealed a complex, multistage PG architecture that develops during septation. Penicillin-binding proteins (PBPs) are essential for the final steps of PG biosynthesis; their transpeptidase activity links the peptide side chains of nascent glycan strands. PBP1 is required for cell division in S. aureus, and here, we demonstrate that it has multiple essential functions associated with its enzymatic activity and as a regulator of division. Loss of PBP1, or just its C-terminal PASTA domains, results in cessation of division at the point of septal plate formation. The PASTA domains can bind PG and thereby potentially coordinate the cell division process. The transpeptidase activity of PBP1 is also essential, but its loss leads to a strikingly different phenotype of thickened and aberrant septa, which is phenocopied by the morphological effects of adding the PBP1-specific beta-lactam, meropenem. Together, these results lead to a model for septal PG synthesis where PBP1 enzyme activity is required for the characteristic architecture of the septum and PBP1 protein molecules enable the formation of the septal plate. IMPORTANCE Bacterial cell wall peptidoglycan is essential, and its synthesis is the target of clinically important antibiotics such as beta-lactams. beta-lactams target penicillin-binding proteins (PBPs) that assemble new peptidoglycan from its building blocks. The human pathogen Staphylococcus aureus only has two essential PBPs that can carry out all the functions necessary for growth and division. In the absence of the confounding antibiotic resistance-associated PBP PBP2A, PBP1 is required for cell division, and here, we have found that it has several essential functions, both as an enzyme and as a coordinator by binding to cell division proteins and to its peptidoglycan product, via its PASTA domains. This has led to a new model for cell division with PBP1 responsible for the synthesis of the characteristic architectural features of the septum.

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