title: The AraC-family regulator GadX enhances multidrug resistance in Escherichia coli by activating expression of mdtEF multidrug efflux genes.
abstract: Multidrug efflux pumps contribute to the resistance of Escherichia coli to many antibiotics and biocides. Here, we report that the AraC-family regulator GadX increases multidrug resistance in E. coli through activation of the MdtEF efflux pump. Screening of random fragments of genomic DNA for ability to increase beta-lactam resistance led to the isolation of a plasmid containing gadX, which codes for the regulator of acid resistance. When overexpressed, gadX significantly increased the resistance of the E. coli strain to oxacillin, cloxacillin, nafcillin, erythromycin, rhodamine 6G, and sodium dodecyl sulfate. The increase in drug resistance caused by gadX overexpression was completely suppressed by deleting the multifunctional outer membrane channel gene tolC. TolC interacts with different drug efflux pumps. Quantitative real-time polymerase chain reaction (PCR) showed that GadX activated the expression of mdtEF but none of the other drug efflux pumps in E. coli. Deletion of mdtEF completely suppressed GadX-mediated multidrug resistance. Our results indicate that the GadX regulator, in addition to its role in acid resistance, increases multidrug resistance in E. coli by activating the MdtEF multidrug efflux pump.
authors.affiliation: Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka, Japan. nishino@sanken.osaka-u.ac.jp
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Nishino
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Senda
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamaguchi
mesh_terms: D051777:AraC Transcription Factor / Q000235:genetics / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial; D004917:Erythromycin / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D010068:Oxacillin / Q000494:pharmacology; D012329:RNA, Bacterial / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012235:Rhodamines / Q000494:pharmacology; D017384:Sequence Deletion; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D051777:AraC Transcription Factor; D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; C446316:GadX protein, E coli; C477834:MdtE protein, E coli; C477833:MdtF protein, E coli; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D012329:RNA, Bacterial; D012235:Rhodamines; D047090:beta-Lactams; C073126:tolC protein, E coli; D012967:Sodium Dodecyl Sulfate; D004917:Erythromycin; D010068:Oxacillin