Blatzer 2015 Antioxid Redox Signal
|Blatzer M, Jukic E, Posch W, Schöpf B, Binder U, Steger M, Blum G, Hackl H, Gnaiger E, Lass-Flörl C, Wilflingseder D (2015) Amphotericin B resistance in Aspergillus terreus is overpowered by co-application of pro-oxidants. Antioxid Redox Signal 23:1424-38.|
Abstract: Invasive fungal infections have significantly increased over the past decades in immune-compromised 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 A. 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.
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 were able to cope better with AmB-induced oxidative stress.
Most importantly, we demonstrate in this study that co-application 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.
Thereby, our study provides novel therapeutic options to treat formerly resistant fungal strains by a combination of AmB and pro-oxidant compounds.
• Keywords: Alternative oxidases
Labels: MiParea: Respiration, mtDNA;mt-genetics, Pharmacology;toxicology
Stress:Oxidative stress;RONS Organism: Fungi
Preparation: Intact cells Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase
Coupling state: ROUTINE Pathway: ROX HRR: Oxygraph-2k