Michael Blatzer1, Emina Jukic1, Wilfried Posch1, Bernd Schöpf2, Ulrike Binder1, Marion Steger1, Gerhard Blum1, Hubert Hackl3, Erich Gnaiger4, Cornelia Lass-Flörl1, Doris Wilflingseder1. 1. 1 Division of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck, Austria . 2. 2 Division of Genetic Epidemiology, Medical University of Innsbruck , Innsbruck, Austria . 3. 3 Division of Bioinformatics, Biocenter, Medical University of Innsbruck , Innsbruck, Austria . 4. 4 D. Swarovski Research Laboratory, Department of General and Transplant Surgery, Medical University of Innsbruck , Innsbruck, Austria .
Abstract
AIMS: 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. INNOVATION: 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. CONCLUSION: Thereby, our study provides novel therapeutic options to treat formerly resistant fungal strains by a combination of AmB and pro-oxidant compounds.
AIMS: 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. INNOVATION: 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. CONCLUSION: Thereby, our study provides novel therapeutic options to treat formerly resistant fungal strains by a combination of AmB and pro-oxidant compounds.
Authors: Kim Vriens; Phalguni Tewari Kumar; Caroline Struyfs; Tanne L Cools; Pieter Spincemaille; Tadej Kokalj; Belém Sampaio-Marques; Paula Ludovico; Jeroen Lammertyn; Bruno P A Cammue; Karin Thevissen Journal: Oxid Med Cell Longev Date: 2017-10-10 Impact factor: 6.543
Authors: Shruthi Satish; Cristina Jiménez-Ortigosa; Yanan Zhao; Min Hee Lee; Enriko Dolgov; Thomas Krüger; Steven Park; David W Denning; Olaf Kniemeyer; Axel A Brakhage; David S Perlin Journal: mBio Date: 2019-06-04 Impact factor: 7.867