title: Potent drugs that attenuate anti-Candida albicans activity of fluconazole and their possible mechanisms of action.
abstract: Fluconazole (FLCZ) is a first-line drug for treating Candida albicans infections, but clinical failure due to reduced sensitivity is a growing concern. Our previous study suggested that certain drug combinations pose a particular challenge in potently reducing FLCZ's anti-C. albicans activity, and cyclooxygenase inhibitors formed the major group of these attenuating drugs in combination with FLCZ. In this study, we examined the effects of diclofenac sodium (DFNa) and related compounds in combination with FLCZ against C. albicans, and investigated their possible mechanisms of interaction. DFNa, ibuprofen, and omeprazole elevated the minimum inhibitory concentration (MIC) of FLCZ by 8-, 4-, and 4-fold, respectively; however, loxoprofen sodium and celecoxib did not. An analogue of DFNa, 2,6-dichlorodiphenylamine, also elevated the MIC by 4-fold. Gene expression analysis revealed that diclofenac sodium induced CDR1 efflux pump activity, but not CDR2 activity. In addition, an efflux pump CDR1 mutant, which was manipulated to not be induced by DFNa, showed less elevation of MIC compared to that shown by the wild type. Therefore, DFNa and related compounds are potent factors for reducing the sensitivity of C. albicans to FLCZ partly via induction of an efflux pump. Although it is not known whether such antagonism is relevant to the clinical treatment failure observed, further investigation of the molecular mechanisms underlying the reduction of FLCZ's anti-C. albicans activity is expected to promote safer and more effective use of the drug.
authors.affiliation: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Urai
authors.affiliation: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Bacteriology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. Electronic address: ykaneko@med.osaka-cu.ac.jp.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Bacteriology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Niki
authors.affiliation: Department of Bacteriology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umeyama
authors.affiliation: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Hidesuke
authors.initials: H
authors.lastname: Fukazawa
authors.affiliation: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ohno
authors.affiliation: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Miyazaki
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000188:drug therapy*; D000068579:Celecoxib / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D015725:Fluconazole / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D005656:Fungal Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D007052:Ibuprofen / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009853:Omeprazole / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology; D054328:Proton Pump Inhibitors / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D016861:Cyclooxygenase Inhibitors; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D010666:Phenylpropionates; D054328:Proton Pump Inhibitors; D004008:Diclofenac; C040656:loxoprofen; D015725:Fluconazole; D000068579:Celecoxib; D009853:Omeprazole; D007052:Ibuprofen
keywords: Candida albicans; Combinatorial effect; Diclofenac; Fluconazole; Ibuprofen; Omeprazole