The increasing number of resistant bacteria is a major threat worldwide, leading to the search for new antibiotic agents. One of the leading strategies is the use of antimicrobial peptides (AMPs), cationic and hydrophobic innate immune defense peptides. A major target of AMPs is the bacterial membrane. Notably, accumulating data suggest that AMPs can activate the two-component systems (TCSs) of Gram-negative bacteria. These include PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB), responsible for remodeling of the bacterial cell surface. To better understand this mechanism, we utilized bacteria deficient either in one system alone or in both and biophysical tools including fluorescence spectroscopy, single-cell atomic force microscopy, electron microscopy, and mass spectrometry (Moskowitz, S. M.; Antimicrob. Agents Chemother. 2012, 56, 1019−1030; Cheng, H. Y.; J. Biomed. Sci. 2010, 17, 60). Our data suggested that the two systems have opposing effects on the properties of Salmonella enterica. The knockout of PhoPQ made the bacteria more susceptible to AMPs by making the surface less rigid, more polarized, and permeable with a slightly more negatively charged cell wall. In addition, the periplasmic space is thinner. In contrast, the knockout of PmrAB did not affect its susceptibility, while it made the bacterial outer layer very rigid, less polarized, and less permeable than the other two mutants, with a negatively charged cell wall similar to the WT. Overall, the data suggest that the coexistence of systems with opposing effects on the biophysical properties of the bacteria contribute to their membrane flexibility, which, on the one hand, is important to accommodate changing environments and, on the other hand, may inhibit the development of meaningful resistance to AMPs.

中文翻译：

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PhoPQ 和 PmrAB 对肠道沙门氏菌鼠伤寒血清型特性的相反影响：对抗菌肽耐药性的影响

越来越多的耐药细菌是世界范围内的主要威胁，导致寻找新的抗生素药物。主要策略之一是使用抗菌肽 (AMP)、阳离子和疏水性先天免疫防御肽。AMPs 的一个主要目标是细菌膜。值得注意的是，越来越多的数据表明 AMP 可以激活革兰氏阴性菌的双组分系统 (TCS)。这些包括 PhoP-PhoQ (PhoPQ) 和 PmrA-PmrB (PmrAB)，负责细菌细胞表面的重塑。为了更好地理解这一机制，我们利用了一个系统单独或两个系统都有缺陷的细菌和生物物理工具，包括荧光光谱、单细胞原子力显微镜、电子显微镜和质谱。莫斯科维茨，SM; 抗微生物。代理Chemother。 2012年56年 1019-1030 年；程海华; J. 生物医学。科学。 2010，17，60）。我们的数据表明这两个系统对沙门氏菌的特性有相反的影响. PhoPQ 的敲除使细菌更容易受到 AMP 的影响，因为它使表面不那么僵硬、极化程度更高，而且细胞壁的负电荷略多，具有渗透性。此外，周质空间更薄。相比之下，PmrAB 的敲除不影响其易感性，同时它使细菌外层非常僵硬，极化程度较低，渗透性低于其他两个突变体，具有类似于 WT 的带负电荷的细胞壁。总体而言，数据表明对细菌生物物理特性具有相反影响的系统的共存有助于它们的膜柔韧性，这一方面对于适应不断变化的环境很重要，另一方面可能会抑制细菌的发育对 AMP 的有意义的抵抗。