title: Synergistic antifungal effect of lactoferrin with azole antifungals against Candida albicans and a proposal for a new treatment method for invasive candidiasis.
abstract: The combination of lactoferrin with fluconazole has been reported to synergistically enhance the antifungal activity of fluconazole against Candida spp. and inhibit the hyphal formation in fluconazole-resistant strains of Candida albicans. In this study, we investigated the association between the therapeutic effects of this combination and the pharmacological characteristics of fluconazole and itraconazole and the variation in these effects with differences among the strains in terms of the susceptibility and resistance mechanisms. Lactoferrin enhanced the growth-inhibitory activity of fluconazole against two different ergosterol mutants but not againt pump mutants or an azole-susceptible strain; but increased the activity of itraconazole against all the strains tested in this study. Exogenous iron cancelled the synergistic effect, which suggests that the iron-chelating function of lactoferrin may contribute to the synergism. Besides, radiolabeled fluconazole assays revealed that lactoferrin did not affect the intracellular concentrations of fluconazole, thereby indicating that these synergistic effects were not due to the alteration of the intracellular uptake of the drug. The development of new clinical treatments and therapeutic method against resistant Candida will depend on our understanding of the resistance mechanisms and methods to overcome them by the application of suitable drug combinations with synergistic effects. The results of this study might contribute to the improvement of our understand of the mechanisms underlying the resistance of Candida strains.
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kakeya
authors.forename: Taiga
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tashiro
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development; D058365:Candidiasis, Invasive / Q000188:drug therapy* / Q000382:microbiology; D004338:Drug Combinations; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology*; D007501:Iron / Q000494:pharmacology; D017964:Itraconazole / Q000494:pharmacology; D007781:Lactoferrin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D017964:Itraconazole; D015725:Fluconazole; D007501:Iron; D007781:Lactoferrin