Demonstration of the role of cell wall homeostasis in Staphylococcus aureus growth and the action of bactericidal antibiotics.
Demonstration of the role of cell wall homeostasis in Staphylococcus aureus growth and the action of bactericidal antibiotics.
复制标题
DOI：
10.1073/pnas.2106022118
复制
发表时间：
2021-11-02
影响因子：
11.1
通讯作者：
Foster SJ
中科院分区：
文献类型：
--
作者：
Salamaga B;Kong L;Pasquina-Lemonche L;Lafage L;von Und Zur Muhlen M;Gibson JF;Grybchuk D;Tooke AK;Panchal V;Culp EJ;Tatham E;O'Kane ME;Catley TE;Renshaw SA;Wright GD;Plevka P;Bullough PA;Han A;Hobbs JK;Foster SJ
细菌细胞壁肽聚糖对于维持活性是必不可少的，但它是动态的，允许生长和分裂。肽聚糖的合成被重要的抗生素抑制，包括β-内酰胺类和万古霉素。使用人类病原体金黄色葡萄球菌，我们研究了肽聚糖稳态机制以及它们是如何中断导致细胞死亡的。这揭示了两种由特定的肽聚糖水解酶介导的抗生素诱导的杀伤机制，两种机制都涉及跨越整个细胞壁厚度的孔的出现。其中一个机制与生长有关，另一个与细胞分裂有关。这项研究支持一个简单的模型，说明细胞如何通过肽聚糖合成和水解的组合来生长，以及抗生素干预如何导致细胞死亡。细菌细胞壁肽聚糖是必不可少的，在面对内部膨胀压力的情况下，保持细胞的完整性和形态。肽聚糖的合成很重要，因为它是包括甲氧西林和万古霉素在内的细胞壁抗生素的靶标。在这里，我们以人类主要病原体金黄色葡萄球菌为例，根据肽聚糖的合成和水解协调的原理，阐明了生长(生命)所必需的细胞壁动态过程以及细胞壁抗生素的杀菌作用(死亡)。金黄色葡萄球菌的死亡是由于对肽聚糖水解酶活性(WalKR)的基本、双组分和正调控系统的耗尽，可以通过添加其他杀菌细胞壁抗生素来防止，从而导致停滞。相比之下，细胞壁抗生素在没有伴随合成的情况下，通过肽聚糖水解酶的活性来杀死人。甲氧西林和万古霉素处理后，由于肽聚糖水解酶的作用，整个细胞壁都会出现穿孔。单用甲氧西林也会导致胞浆分离和畸形间隔，并涉及主要的肽聚糖水解酶AT1，这一过程可被万古霉素抑制。万古霉素的杀菌作用涉及肽聚糖水解酶SAGB。在细胞壁抗生素存在的情况下，用抑制剂Complestatin抑制肽聚糖水解酶的活性可以减少杀伤力，而相反，通过失去壁磷壁酸而解除对水解酶活性的调节会增加死亡率。对于金黄色葡萄球菌来说，对细胞壁合成和水解的独立调控可以导致细胞生长、死亡或停滞，这对开发这种重要病原体的新控制机制具有重要意义。
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.
登录
查看更多内容
影响因子：
4
作者：
Farha, Maya A.;Leung, Alexander;Sewell, Edward W.;D'Elia, Michael A.;Allison, Sarah E.;Ejim, Linda;Pereira, Pedro M.;Pinho, Mariana G.;Wright, Gerard D.;Brown, Eric D.
通讯作者：
Brown, Eric D.
影响因子：
2.8
作者：
Adhikari, RP;Novick, RP
通讯作者：
Novick, RP
DOI：
10.1099/00221287-6-1-2-95
发表时间：
1952-01-01
期刊：
JOURNAL OF GENERAL MICROBIOLOGY
影响因子：
--
作者：
DUTHIE, ES;LORENZ, LL
通讯作者：
LORENZ, LL
影响因子：
3.6
作者：
Dubrac, Sarah;Bisicchia, Paola;Msadek, Tarek
通讯作者：
Msadek, Tarek
影响因子：
64.5
作者：
Kohanski, Michael A.;Dwyer, Daniel J.;Collins, James J.
通讯作者：
Collins, James J.