The polyene antifungals, amphotericin B and nystatin, cause cell death in Saccharomyces cerevisiae by a distinct mechanism to amphibian-derived antimicrobial peptides

Background: There is a pressing need to identify novel antifungal drug targets to aid in the therapy of life-threatening mycoses and overcome increasing drug resistance. Identifying specific mechanisms of action of membrane-interacting antimicrobial drugs on the model fungus Saccharomyces cerevisiae is one avenue towards addressing this issue. The S. cerevisiae deletion mutants Deltaizh2, Deltaizh3, Deltaaif1 and Deltastm1 were demonstrated to be resistant to amphibian-derived antimicrobial peptides (AMPs). The purpose of this study was to examine whether AMPs and polyene antifungals have a similar mode of action; this was done by comparing the relative tolerance of the mutants listed above to both classes of antifungal. Findings: In support of previous findings on solid media it was shown that Deltaizh2 and Deltaizh3 mutants had increased resistance to both amphotericin B (1-2 mug ml-1) and nystatin (2.5 - 5 mug ml-1) in liquid culture, after acute exposure. However, Deltaaif1 and Deltastm1 had wild-type levels of susceptibility to these polyenes. The generation of reactive oxygen species (ROS) after exposure to amphotericin B was also reduced in Deltaizh2 and Deltaizh3. These data indicated that polyene antifungal and AMPs may act via distinct mechanisms of inducing cell death in S. cerevisiae. Conclusions: Further understanding of the mechanism(s) involved in causing cell death and the roles of IZH2 and IZH3 in drug susceptibility may help to inform improved drug design and treatment of fungal pathogens.