title: The Cpx stress response confers resistance to some, but not all, bactericidal antibiotics.
abstract: 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∼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 β-lactams than wild-type cells. Thus, it seems unlikely that all bactericidal antibiotics kill by the same mechanism.
authors: Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
authors: Tara F
authors: TF
authors: Mahoney
authors: Thomas J
authors: TJ
authors: Silhavy
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D006918:Hydroxyurea / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D006918:Hydroxyurea