CpxR Activates MexAB-OprM Efflux Pump Expression and Enhances Antibiotic Resistance in Both Laboratory and Clinical nalB-Type Isolates of Pseudomonas aeruginosa

• Published in: PLoS pathogens Vol. 12; no. 10; p. e1005932
• Main Authors: Tian, Zhe-Xian, Yi, Xue-Xian, Cho, Anna, O'Gara, Fergal, Wang, Yi-Ping
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Bacterial Outer Membrane Proteins - biosynthesis; Bacterial Proteins - metabolism; Binding sites; Biology and Life Sciences; Blotting, Western; Colleges & universities; Drug resistance; Drug Resistance, Microbial - physiology; Drug Resistance, Multiple - physiology; Electrophoretic Mobility Shift Assay; Escherichia coli; Gene expression; Gene Knockout Techniques; Genes; Genetic aspects; Humans; Medicine and Health Sciences; Membrane Transport Proteins - biosynthesis; Microbial drug resistance; Microbial Sensitivity Tests; Physiological aspects; Protection and preservation; Pseudomonas aeruginosa; Pseudomonas Infections - metabolism; Real-Time Polymerase Chain Reaction; Research and Analysis Methods; Beijing China
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005932

Resistance-Nodulation-Division (RND) efflux pumps are responsible for multidrug resistance in Pseudomonas aeruginosa. In this study, we demonstrate that CpxR, previously identified as a regulator of the cell envelope stress response in Escherichia coli, is directly involved in activation of expression of RND efflux pump MexAB-OprM in P. aeruginosa. A conserved CpxR binding site was identified upstream of the mexA promoter in all genome-sequenced P. aeruginosa strains. CpxR is required to enhance mexAB-oprM expression and drug resistance, in the absence of repressor MexR, in P. aeruginosa strains PA14. As defective mexR is a genetic trait associated with the clinical emergence of nalB-type multidrug resistance in P. aeruginosa during antibiotic treatment, we investigated the involvement of CpxR in regulating multidrug resistance among resistant isolates generated in the laboratory via antibiotic treatment and collected in clinical settings. CpxR is required to activate expression of mexAB-oprM and enhances drug resistance, in the absence or presence of MexR, in ofloxacin-cefsulodin-resistant isolates generated in the laboratory. Furthermore, CpxR was also important in the mexR-defective clinical isolates. The newly identified regulatory linkage between CpxR and the MexAB-OprM efflux pump highlights the presence of a complex regulatory network modulating multidrug resistance in P. aeruginosa.