In addition to the fungal cellular membrane, the cellular antioxidant system can also be a viable target in the antifungal action of amphotericin B (AMB). Co-application of certain redox-potent natural compounds with AMB actually increases efficacy of the drug through chemosensitization. Some redox-potent chemosensitizers and AMB perturb common cellular targets, resulting in synergistic inhibition of fungal growth. Chemosensitizing activities of four redox-potent benzaldehydes were tested against clinical and reference strains of Candida albicans, C. krusei, C. tropicalis, and Cryptococcus neoformans in combination with AMB, based on assays outlined by the European Committee on Antimicrobial Susceptibility Testing. Two dihydroxybenzaldehydes (DHBAs), i.e., 2,3-DHBA and 2,5-DHBA, significantly enhanced activity of AMB against most strains, as measured by lower minimum inhibitory concentrations and/or minimum fungicidal concentrations (MFCs). A non-hydroxylated benzaldehyde, trans-cinnamaldehyde, showed chemosensitizing activity through lower MFCs, only. Contrastingly, a methoxylated benzaldehyde (3,5-dimethoxybenzaldehyde) had no chemosensitizing activity, as all strains were hypertolerant to this compound. Bioassays using deletion mutants of the model yeast, Saccharomyces cerevisiae, indicated DHBAs exerted their chemosensitizing activity by targeting mitochondrial superoxide dismutase. This targeting, in turn, disrupted the ability of the yeast strains to respond to AMB-induced oxidative stress. These in vitro results indicate that certain DHBAs are potent chemosensitizing agents to AMB through co-disruption of the oxidative stress response capacity of yeasts. Such redox-potent compounds show promise for enhancing AMB-based antifungal therapy for candidiasis and cryptococcosis.
Keywords: amphotericin B, dihydroxybenzaldehydes, chemosensitization, Candida, Cryptococcus, antioxidant system, superoxide dismutase
Citation: Kim JH, Faria NCG, Martins MDL, Chan KL and Campbell BC (2012) Enhancement of antimycotic activity of amphotericin B by targeting the oxidative stress response of Candida and Cryptococcus with natural dihydroxybenzaldehydes. Front. Microbio. 3:261. doi: 10.3389/fmicb.2012.00261
Received: 23 May 2012; Accepted: 03 July 2012;
Published online: 19 July 2012.
Edited by:Mirian A. F. Hayashi, Federal University of São Paulo, Brazil
Reviewed by:Fernando César Bizerra, Federal University of São Paulo, Brazil
Copyright: © 2012 Kim, Faria, Martins, Chan and Campbell. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Bruce C. Campbell, Plant Mycotoxin Research Unit, Western Regional Research Center, United States Department of Agriculture, Agricultural Research Service, 800 Buchanan Street, Albany, CA 94710, USA. e-mail: email@example.com