Synergistic combination of direct plasma membrane damage and oxidative stress as a cause of antifungal activity of polyol macrolide antibiotic niphimycin.
The polyol macrolide niphimycin (NM) exhibited fungicidal activity against Saccharomyces cerevisiae cells accompanying the leakage of cytoplasmic components including nucleotide-like materials in addition to K+ at 10 microM or above. Such a dynamic change in the plasma membrane was observed upon treatment of cells with H2O2 but not with the polyene macrolide antibiotic amphotericin B (AmB). The NM-induced cell death could be prevented by the exogenous addition of phosphatidylcholine (PC) whereas such a protective effect was only weakly observed with ergosterol, the molecular target of AmB. NM-treated cells were further characterized with a dramatic loss of glutathione even at a dose of 5 microM or less, representing NM-triggered metabolic conversion of the antioxidant molecule. NM-treatment indeed accelerated the cellular production of reactive oxygen species (ROS) such as H2O2 detectable with a specific fluorescent probe in a dose-dependent manner. These results suggested a synergistic combination of direct plasma membrane damage and oxidative stress as a cause of antifungal activity of NM against S. cerevisiae.
Nakayama
Keiji
K
Department of Bio- and Geoscience, Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
Yamaguchi
Takafumi
T
Doi
Takeshi
T
Usuki
Yoshinosuke
Y
Taniguchi
Makoto
M
Tanaka
Toshio
T