The Cpx Stress Response Confers Resistance to Some, but Not All, Bactericidal Antibiotics
The Cpx Stress Response Confers Resistance to Some, but Not All, Bactericidal Antibiotics
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DOI：
10.1128/jb.02197-12
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发表时间：
2013-05-01
影响因子：
3.2
通讯作者：
Silhavy, Thomas J.
中科院分区：
文献类型：
--
作者：
Mahoney, Tara F.;Silhavy, Thomas J.
最近有人提出，杀菌抗生素，包括氨基糖苷类抗生素 (AGA) 和有毒小分子，如羟基脲 (HU)，以同样的方式杀死细菌，即通过需要激活 Cpx 应激反应的过程产生活性氧 (ROS)。我们建议 Cpx 发挥相反的保护作用。我们已经证实了初步发现，cpxA 无效突变赋予 HU 抗性。然而，双组分传感器 CpxA 既是激酶又是磷酸酶，我们实验室之前的工作表明，去除 CpxA 可以激活应激反应，因为磷酸化反应调节剂（CpxR 类似于 P）的积聚会在磷酸酶活性缺失的情况下发生。我们发现，显性的 cpxA* 突变持续激活 Cpx 应激反应，以 CpxR 依赖性方式赋予对 HU 和 AGA 的高水平抗性。相反，通过突变磷酸化位点 (D51A) 或假定的 DNA 结合基序 (M199A) 来灭活 CpxR 反应调节因子不会增加对 HU 或 AGA 的抗性。综上所述，这些结果表明 Cpx 应激反应的激活可以保护细胞免受 HU 和 AGA 的侵害。然而，Cpx 反应不会增加对所有类别杀菌抗生素的耐药性，因为 cpxA* 突变体对氟喹诺酮类药物或 β-内酰胺类药物的耐药性并不比野生型细胞明显更强。因此，所有杀菌抗生素似乎不太可能通过相同的机制来杀死细菌。
It has recently been suggested that bactericidal antibiotics, including aminoglycoside antibiotics (AGAs), and toxic small molecules, such as hydroxyurea (HU), kill bacteria the same way, namely, by generating reactive oxygen species (ROS) via a process requiring activation of the Cpx stress response. We suggest an opposite, protective role for Cpx. We have confirmed the initial finding that cpxA null mutations confer resistance to HU. However, the two-component sensor CpxA is both a kinase and a phosphatase, and previous work from our lab has shown that removing CpxA can activate the stress response owing to buildup of the phosphorylated response regulator (CpxR similar to P) that occurs in the absence of the phosphatase activity. We show that a dominant cpxA* mutation that constitutively activates the Cpx stress response confers a high level of resistance to both HU and AGAs in a CpxR-dependent manner. In contrast, inactivating the CpxR response regulator by mutating the phosphorylation site (D51A) or the putative DNA-binding motif (M199A) does not increase resistance to HU or AGAs. Taken together, these results demonstrate that activation of the Cpx stress response can protect cells from HU and AGAs. However, the Cpx response does not increase resistance to all classes of bactericidal antibiotics, as the cpxA* mutants are not significantly more resistant to fluoroquinolones or beta-lactams than wild-type cells. Thus, it seems unlikely that all bactericidal antibiotics kill by the same mechanism.