title: Enhancement effect of N-methyl-N″-dodecylguanidine on the vacuole-targeting fungicidal activity of amphotericin B against the pathogenic fungus Candida albicans.
abstract: The alkylguanidium chain attached to the polyol lactone ring of niphimycin (NM) is considered a requisite for the fungicidal activity of NM characterized by vacuole membrane fragmentation and oxidative stress induction. The addition of N-methyl-N″-dodecylguanidine to the medium can enhance the vacuole-targeting fungicidal activity of amphotericin B (AmB), in which the lactone ring has no such alkylguanidium chain, on Saccharomyces cerevisiae cells. In this study, the enhancement effect of N-methyl-N″-dodecylguanidine on the vacuole-targeting fungicidal activity of AmB was examined against Candida albicans in RPMI 1640 medium at 37  °C. N-methyl-N″-dodecylguanidine was lethal to C. albicans cells and additionally enhanced the vacuole disruptive activity of AmB against this pathogenic fungus. N-methyl-N″-dodecylguanidine elevated the generation of cellular reactive oxygen species when added alone in a dose-dependent manner, but its enhancement effect on AmB lethality did not accompany amplification of oxidative stress induction. The fungal vacuoles were protected against the disruptive damage even if cells were treated with H(2)O(2) alone at a lethal concentration or treated with H(2)O(2) at a sublethal concentration in combination with AmB. N-methyl-N″-dodecylguanidine was ineffective in enhancing AmB lethality or AmB-induced vacuole disruption when cells had been pretreated with ergosterol. Ergosterol-dependent mechanism is thus considered to be a possible target of N-methyl-N″-dodecylguanidine in enhancing the vacuole-targeting fungicidal activity of AmB in C. albicans cells.
authors.affiliation: Department of Biology and Geosciences, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yutani
authors.forename: Akira
authors.initials: A
authors.lastname: Ogita
authors.forename: Yoshinosuke
authors.initials: Y
authors.lastname: Usuki
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004357:Drug Synergism; D004875:Ergosterol / Q000494:pharmacology; D006146:Guanidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000008:administration & dosage / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D006146:Guanidines; C518890:N-methyl-N''-dodecylguanidine; D017382:Reactive Oxygen Species; C010492:niphimycin; D000666:Amphotericin B; D006861:Hydrogen Peroxide; D004875:Ergosterol