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Oxidative Medicine and Cellular Longevity
Volume 2017 (2017), Article ID 4064628, 17 pages
https://doi.org/10.1155/2017/4064628
Research Article

Increasing the Fungicidal Action of Amphotericin B by Inhibiting the Nitric Oxide-Dependent Tolerance Pathway

1Centre of Microbial and Plant Genetics, KU Leuven, 3001 Heverlee, Belgium
2BIOSYST-MEBIOS, KU Leuven, 3001 Heverlee, Belgium
3VIB Department of Plant Systems Biology, 9052 Ghent, Belgium
4Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
5Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
6ICVS/3B’s-PT Government Associate Laboratory, Braga/Guimarães, Portugal

Correspondence should be addressed to Bruno P. A. Cammue

Received 18 May 2017; Accepted 2 August 2017; Published 10 October 2017

Academic Editor: Reiko Matsui

Copyright © 2017 Kim Vriens et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Amphotericin B (AmB) induces oxidative and nitrosative stresses, characterized by production of reactive oxygen and nitrogen species, in fungi. Yet, how these toxic species contribute to AmB-induced fungal cell death is unclear. We investigated the role of superoxide and nitric oxide radicals in AmB’s fungicidal activity in Saccharomyces cerevisiae, using a digital microfluidic platform, which enabled monitoring individual cells at a spatiotemporal resolution, and plating assays. The nitric oxide synthase inhibitor L-NAME was used to interfere with nitric oxide radical production. L-NAME increased and accelerated AmB-induced accumulation of superoxide radicals, membrane permeabilization, and loss of proliferative capacity in S. cerevisiae. In contrast, the nitric oxide donor S-nitrosoglutathione inhibited AmB’s action. Hence, superoxide radicals were important for AmB’s fungicidal action, whereas nitric oxide radicals mediated tolerance towards AmB. Finally, also the human pathogens Candida albicans and Candida glabrata were more susceptible to AmB in the presence of L-NAME, pointing to the potential of AmB-L-NAME combination therapy to treat fungal infections.