期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：44
DOI：10.1073/pnas.2106022118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The bacterial cell wall peptidoglycan is essential for maintenance of viability and yet is dynamic, permitting growth and division. Peptidoglycan synthesis is inhibited by important antibiotics, including β-lactams and vancomycin. Using the human pathogen
Staphylococcus aureus, we have examined peptidoglycan homeostatic mechanisms and how their interruption leads to cell death. This has revealed two antibiotic-induced killing mechanisms mediated by specific peptidoglycan hydrolases, both involving the appearance of holes that span the entire thickness of the cell wall. One of the mechanisms is associated with growth and the other with cell division. This study supports a simple model for how cells grow via a combination of peptidoglycan synthesis and hydrolysis and how antibiotic intervention leads to cell death.
Bacterial cell wall peptidoglycan is essential, maintaining both cellular integrity and morphology, in the face of internal turgor pressure. Peptidoglycan synthesis is important, as it is targeted by cell wall antibiotics, including methicillin and vancomycin. Here, we have used the major human pathogen
Staphylococcus aureus to elucidate both the cell wall dynamic processes essential for growth (life) and the bactericidal effects of cell wall antibiotics (death) based on the principle of coordinated peptidoglycan synthesis and hydrolysis. The death of
S. aureus due to depletion of the essential, two-component and positive regulatory system for peptidoglycan hydrolase activity (WalKR) is prevented by addition of otherwise bactericidal cell wall antibiotics, resulting in stasis. In contrast, cell wall antibiotics kill via the activity of peptidoglycan hydrolases in the absence of concomitant synthesis. Both methicillin and vancomycin treatment lead to the appearance of perforating holes throughout the cell wall due to peptidoglycan hydrolases. Methicillin alone also results in plasmolysis and misshapen septa with the involvement of the major peptidoglycan hydrolase Atl, a process that is inhibited by vancomycin. The bactericidal effect of vancomycin involves the peptidoglycan hydrolase SagB. In the presence of cell wall antibiotics, the inhibition of peptidoglycan hydrolase activity using the inhibitor complestatin results in reduced killing, while, conversely, the deregulation of hydrolase activity via loss of wall teichoic acids increases the death rate. For
S. aureus, the independent regulation of cell wall synthesis and hydrolysis can lead to cell growth, death, or stasis, with implications for the development of new control regimes for this important pathogen.
