title: CpxR Activates MexAB-OprM Efflux Pump Expression and Enhances Antibiotic Resistance in Both Laboratory and Clinical nalB-Type Isolates of Pseudomonas aeruginosa.
abstract: 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.
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Zhe-Xian
authors.identifier: http://orcid.org/0000-0003-2498-8087
authors.initials: ZX
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Xue-Xian
authors.initials: XX
authors.lastname: Yi
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Anna
authors.identifier: http://orcid.org/0000-0001-8863-0784
authors.initials: A
authors.lastname: Cho
authors.affiliation: BIOMERIT Research Centre, Department of Microbiology, University College Cork, Cork, Ireland.|School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
authors.forename: Fergal
authors.initials: F
authors.lastname: O'Gara
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Wang
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000096:biosynthesis; D001426:Bacterial Proteins / Q000378:metabolism*; D015153:Blotting, Western; D004352:Drug Resistance, Microbial / Q000502:physiology*; D018432:Drug Resistance, Multiple / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D055786:Gene Knockout Techniques; D006801:Humans; D026901:Membrane Transport Proteins / Q000096:biosynthesis; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000378:metabolism*; D011550:Pseudomonas aeruginosa; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; C085504:CpxR protein, Bacteria