title: Amphotericin B Resistance in Aspergillus terreus Is Overpowered by Coapplication of Pro-oxidants.
abstract: OBJECTIVE
  Invasive fungal infections have significantly increased over the past decades in immunocompromised individuals and high-risk patients. Amphotericin B (AmB) exerts a powerful and broad activity against a vast array of fungi and has a remarkably low rate of microbial resistance. However, most isolates of Aspergillus terreus developed an intrinsic resistance against AmB, and during this study, we characterized the mode of action of this polyene antifungal drug in more detail in resistant (ATR) and rare susceptible (ATS) clinical isolates of A. terreus.
  
  
  RESULTS
  We illustrate that AmB treatment changes cellular redox status and promotes the generation of high levels of reactive oxygen species (ROS) in ATS. In contrast, ATR isolates were able to cope better with AmB-induced oxidative stress.
  
  
  METHODS
  Most importantly, we demonstrate in this study that coapplication of anti- and pro-oxidants significantly affects AmB efficacy in an antithetic manner--antioxidants and ROS-scavenging agents increase AmB tolerance in susceptible strains, while pro-oxidants render formerly resistant isolates considerably susceptible to the antifungal drug also in vivo in a Galleria animal model.
  
  
  CONCLUSIONS
  Thereby, our study provides novel therapeutic options to treat formerly resistant fungal strains by a combination of AmB and pro-oxidant compounds.
authors.affiliation: 1 Division of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Michael
authors.initials: M
authors.lastname: Blatzer
authors.affiliation: 1 Division of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Emina
authors.initials: E
authors.lastname: Jukic
authors.affiliation: 1 Division of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Wilfried
authors.initials: W
authors.lastname: Posch
authors.affiliation: 2 Division of Genetic Epidemiology, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Bernd
authors.initials: B
authors.lastname: Schöpf
authors.affiliation: 1 Division of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Ulrike
authors.initials: U
authors.lastname: Binder
authors.affiliation: 1 Division of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Marion
authors.initials: M
authors.lastname: Steger
authors.affiliation: 1 Division of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Gerhard
authors.initials: G
authors.lastname: Blum
authors.affiliation: 3 Division of Bioinformatics, Biocenter, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Hubert
authors.initials: H
authors.lastname: Hackl
authors.affiliation: 4 D. Swarovski Research Laboratory, Department of General and Transplant Surgery, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Erich
authors.initials: E
authors.lastname: Gnaiger
authors.affiliation: 1 Division of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lass-Flörl
authors.affiliation: 1 Division of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck, Austria .
authors.forename: Doris
authors.initials: D
authors.lastname: Wilflingseder
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000187:drug effects; D025141:Drug Resistance, Fungal; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D010101:Oxygen Consumption / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D000666:Amphotericin B