Dörr Tobias, Alvarez Laura, Delgado Fernanda, Davis Brigid M, Cava Felipe, Waldor Matthew K
Howard Hughes Medical Institute, Brigham and Women's Hospital Division of Infectious Diseases and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
Laboratory for Molecular Infection Medicine Sweden, Department of Molecular Biology, Umeå Centre for Microbial Research, Umeå University, 90187 Umeå, Sweden.
Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):404-9. doi: 10.1073/pnas.1520333113. Epub 2015 Dec 28.
The bacterial cell wall is critical for maintenance of cell shape and survival. Following exposure to antibiotics that target enzymes required for cell wall synthesis, bacteria typically lyse. Although several cell envelope stress response systems have been well described, there is little knowledge of systems that modulate cell wall synthesis in response to cell wall damage, particularly in Gram-negative bacteria. Here we describe WigK/WigR, a histidine kinase/response regulator pair that enables Vibrio cholerae, the cholera pathogen, to survive exposure to antibiotics targeting cell wall synthesis in vitro and during infection. Unlike wild-type V. cholerae, mutants lacking wigR fail to recover following exposure to cell-wall-acting antibiotics, and they exhibit a drastically increased cell diameter in the absence of such antibiotics. Conversely, overexpression of wigR leads to cell slimming. Overexpression of activated WigR also results in increased expression of the full set of cell wall synthesis genes and to elevated cell wall content. WigKR-dependent expression of cell wall synthesis genes is induced by various cell-wall-acting antibiotics as well as by overexpression of an endogenous cell wall hydrolase. Thus, WigKR appears to monitor cell wall integrity and to enhance the capacity for increased cell wall production in response to damage. Taken together, these findings implicate WigKR as a regulator of cell wall synthesis that controls cell wall homeostasis in response to antibiotics and likely during normal growth as well.
细菌细胞壁对于维持细胞形状和生存至关重要。在接触针对细胞壁合成所需酶的抗生素后，细菌通常会裂解。尽管已经对几种细胞包膜应激反应系统进行了充分描述，但对于响应细胞壁损伤而调节细胞壁合成的系统却知之甚少，尤其是在革兰氏阴性菌中。在此，我们描述了WigK/WigR，这是一对组氨酸激酶/反应调节因子，它使霍乱病原体霍乱弧菌能够在体外和感染期间暴露于针对细胞壁合成的抗生素后存活下来。与野生型霍乱弧菌不同，缺乏wigR的突变体在接触作用于细胞壁的抗生素后无法恢复，并且在没有此类抗生素的情况下，它们的细胞直径会大幅增加。相反，wigR的过表达会导致细胞变细。活化的WigR的过表达还会导致全套细胞壁合成基因的表达增加以及细胞壁含量升高。细胞壁合成基因的WigKR依赖性表达可由各种作用于细胞壁的抗生素以及内源性细胞壁水解酶的过表达诱导。因此，WigKR似乎在监测细胞壁完整性，并增强响应损伤而增加细胞壁产生的能力。综上所述，这些发现表明WigKR是一种细胞壁合成调节因子，它在响应抗生素时以及可能在正常生长过程中控制细胞壁稳态。
