title: Enhanced active efflux, repression of porin synthesis and development of Mar phenotype by diazepam in two enterobacteria strains.
abstract: The aim of this work was to determine whether diazepam could induce the multiple antibiotic resistance (Mar) phenotype in Klebsiella pneumoniae and Escherichia coli strains. The Mar phenotype is characterized by decreased susceptibility to multiple antibiotics due to the loss of porins and/or increased expression of active efflux systems. The effect of subinhibitory concentrations of diazepam on the susceptibility of different antimicrobial agents, outer-membrane protein expression and norfloxacin intracellular accumulation was studied. The results revealed that diazepam concentrations equal or twice adult dosage induced the same Mar phenotype as two well known E. coli marRAB inducers, sodium salicylate and sodium benzoate. Susceptibility to norfloxacin in a K. pneumoniae clinical isolate and E. coli strain Ag100 decreased due to enhanced active efflux and loss of porin expression. A decreased susceptibility to chloramphenicol, tetracycline, nalidixic acid and beta-lactam antibiotics was also observed. In conclusion, like sodium salicylate or sodium benzoate, diazepam may induce the Mar phenotype.
authors.affiliation: Microbiology, Department of Clinical Sciences, School of Medicine, University of Las Palmas de G. C., Dr. Pasteur, 35080 Las Palmas, Spain 2Department of Microbiology, Hospital Clinic, IDIBAPS, School of Medicine, University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain 3Department of Science and Biomedical Technology, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: María M
authors.initials: MM
authors.lastname: Tavío
authors.affiliation: Microbiology, Department of Clinical Sciences, School of Medicine, University of Las Palmas de G. C., Dr. Pasteur, 35080 Las Palmas, Spain 2Department of Microbiology, Hospital Clinic, IDIBAPS, School of Medicine, University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain 3Department of Science and Biomedical Technology, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Jordi
authors.initials: J
authors.lastname: Vila
authors.affiliation: Microbiology, Department of Clinical Sciences, School of Medicine, University of Las Palmas de G. C., Dr. Pasteur, 35080 Las Palmas, Spain 2Department of Microbiology, Hospital Clinic, IDIBAPS, School of Medicine, University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain 3Department of Science and Biomedical Technology, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Perilli
authors.affiliation: Microbiology, Department of Clinical Sciences, School of Medicine, University of Las Palmas de G. C., Dr. Pasteur, 35080 Las Palmas, Spain 2Department of Microbiology, Hospital Clinic, IDIBAPS, School of Medicine, University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain 3Department of Science and Biomedical Technology, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Lucía T
authors.initials: LT
authors.lastname: Casañas
authors.affiliation: Microbiology, Department of Clinical Sciences, School of Medicine, University of Las Palmas de G. C., Dr. Pasteur, 35080 Las Palmas, Spain 2Department of Microbiology, Hospital Clinic, IDIBAPS, School of Medicine, University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain 3Department of Science and Biomedical Technology, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Maciá
authors.affiliation: Microbiology, Department of Clinical Sciences, School of Medicine, University of Las Palmas de G. C., Dr. Pasteur, 35080 Las Palmas, Spain 2Department of Microbiology, Hospital Clinic, IDIBAPS, School of Medicine, University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain 3Department of Science and Biomedical Technology, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Amicosante
authors.affiliation: Microbiology, Department of Clinical Sciences, School of Medicine, University of Las Palmas de G. C., Dr. Pasteur, 35080 Las Palmas, Spain 2Department of Microbiology, Hospital Clinic, IDIBAPS, School of Medicine, University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain 3Department of Science and Biomedical Technology, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: María T
authors.initials: MT
authors.lastname: Jiménez de Anta
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000096:biosynthesis*; D001693:Biological Transport, Active / Q000187:drug effects; D003593:Cytoplasm / Q000737:chemistry; D003975:Diazepam / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D020536:Enzyme Activators / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009643:Norfloxacin / Q000378:metabolism* / Q000494:pharmacology; D018272:Porins / Q000096:biosynthesis; D020160:Sodium Benzoate / Q000494:pharmacology; D012980:Sodium Salicylate / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D020536:Enzyme Activators; C109237:OmpF protein; D018272:Porins; D009643:Norfloxacin; D020160:Sodium Benzoate; D003975:Diazepam; D012980:Sodium Salicylate