Increasing the Fungicidal Action of Amphotericin B by Inhibiting the Nitric Oxide-Dependent Tolerance Pathway

Figure 9

Schematic overview of the major findings on AmB mechanism of action in this study. Within 15 min, AmB caused cell cycle arrest in the G2/M phase and induced a yet to be elucidated event X, the latter leading to loss of proliferative capacity in yeast. These effects were independent of nitric oxide radicals, superoxide anion radicals, and membrane permeabilization. After 30 min, AmB induced the accumulation of superoxide radicals, which was associated with membrane permeabilization and loss of proliferative capacity in yeast, and was partially blocked by beneficial action of nitric oxide radicals. Interestingly, the combinatorial action of AmB and L-NAME induced a yet to be identified event Y within 15 min, which was independent of nitric oxide radicals, and enhanced the effect of event X, leading to enhanced loss of proliferative capacity in yeast.