Amphotericin B Resistance in Aspergillus terreus Is Overpowered by Coapplication of Pro-oxidants

作者：Blatzer Michael; Jukic Emina; Posch Wilfried; Schoepf Bernd; Binder Ulrike; Steger Marion; Blum Gerhard; Hackl Hubert; Gnaiger Erich; Lass Floerl Cornelia; Wilflingseder Doris^*

来源：Antioxidants and Redox Signaling, 2015, 23(18): 1424-1438.

DOI：10.1089/ars.2014.6220

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 mannerantioxidants 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. Antioxid. Redox Signal. 23, 1424-1438.

• 出版日期2015-12-20