title: The polyene antifungals, amphotericin B and nystatin, cause cell death in Saccharomyces cerevisiae by a distinct mechanism to amphibian-derived antimicrobial peptides.
abstract: 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 Δizh2, Δizh3, Δaif1 and Δstm1 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.
  
  
  RESULTS
  In support of previous findings on solid media it was shown that Δizh2 and Δizh3 mutants had increased resistance to both amphotericin B (1-2 μg ml-1) and nystatin (2.5 - 5 μg ml-1) in liquid culture, after acute exposure. However, Δaif1 and Δstm1 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 Δizh2 and Δizh3. 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.
authors.forename: George
authors.initials: G
authors.lastname: Serhan
authors.forename: Colin M
authors.initials: CM
authors.lastname: Stack
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Perrone
authors.affiliation: University of Western Sydney, School of Science and Health, Campbelltown Campus, Narellan Road, Campbelltown, NSW 2560, Australia. o.morton@uws.edu.au.
authors.forename: Charles Oliver
authors.initials: CO
authors.lastname: Morton
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D017353:Gene Deletion; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D009761:Nystatin / Q000494:pharmacology*; D011090:Polyenes / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; D011090:Polyenes; D009761:Nystatin; D000666:Amphotericin B