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Open AccessArticle

Targeting the Mitochondrial Respiratory Chain of Cryptococcus through Antifungal Chemosensitization: A Model for Control of Non-Fermentative Pathogens

1
Plant Mycotoxin Research Unit, Western Regional Research Center, USDA-ARS, 800 Buchanan St., Albany, CA 94710, USA
2
Instituto de Higiene e Medicina Tropical/CREM, Universidade Nova de Lisboa, Portugal
*
Author to whom correspondence should be addressed.
Molecules 2013, 18(8), 8873-8894; https://doi.org/10.3390/molecules18088873
Received: 4 July 2013 / Revised: 19 July 2013 / Accepted: 22 July 2013 / Published: 25 July 2013
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
Enhanced control of species of Cryptococcus, non-fermentative yeast pathogens, was achieved by chemosensitization through co-application of certain compounds with a conventional antimicrobial drug. The species of Cryptococcus tested showed higher sensitivity to mitochondrial respiratory chain (MRC) inhibition compared to species of Candida. This higher sensitivity results from the inability of Cryptococcus to generate cellular energy through fermentation. To heighten disruption of cellular MRC, octyl gallate (OG) or 2,3-dihydroxybenzaldehyde (2,3-DHBA), phenolic compounds inhibiting mitochondrial functions, were selected as chemosensitizers to pyraclostrobin (PCS; an inhibitor of complex III of MRC). The cryptococci were more susceptible to the chemosensitization (i.e., PCS + OG or 2,3-DHBA) than the Candida with all Cryptococcus strains tested being sensitive to this chemosensitization. Alternatively, only few of the Candida strains showed sensitivity. OG possessed higher chemosensitizing potency than 2,3-DHBA, where the concentration of OG required with the drug to achieve chemosensitizing synergism was much lower than that required of 2,3-DHBA. Bioassays with gene deletion mutants of the model yeast Saccharomyces cerevisiae showed that OG or 2,3-DHBA affect different cellular targets. These assays revealed mitochondrial superoxide dismutase or glutathione homeostasis plays a relatively greater role in fungal tolerance to 2,3-DHBA or OG, respectively. These findings show that application of chemosensitizing compounds that augment MRC debilitation is a promising strategy to antifungal control against yeast pathogens. View Full-Text
Keywords: chemosensitization; Cryptococcus; Candida; Saccharomyces; octyl gallate; 2,3-dihydroxybenzaldehyde; mitochondrial respiration inhibitors chemosensitization; Cryptococcus; Candida; Saccharomyces; octyl gallate; 2,3-dihydroxybenzaldehyde; mitochondrial respiration inhibitors
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Kim, J.H.; Haff, R.P.; Faria, N.C.G.; Martins, M.D.L.; Chan, K.L.; Campbell, B.C. Targeting the Mitochondrial Respiratory Chain of Cryptococcus through Antifungal Chemosensitization: A Model for Control of Non-Fermentative Pathogens. Molecules 2013, 18, 8873-8894.

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