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Title: Enhanced activity of antifungal drugs using natural phenolics against yeast strains of Candida and Cryptococcus

item FARIA, NATALIA - University Of Lisbon
item Kim, Jong Heon
item GONCALVES, LUZIA - University Of Lisbon
item MARTINS, MARIE DE LUZ - University Of Lisbon
item Chan, Kathleen - Kathy
item Campbell, Bruce

Submitted to: Letters in Applied Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/15/2011
Publication Date: 4/15/2011
Citation: Faria, N.C., Kim, J.H., Goncalves, L., Martins, M., Chan, K.L., Campbell, B.C. 2011. Enhanced activity of antifungal drugs using natural phenolics against yeast strains of Candida and Cryptococcus. Letters in Applied Microbiology. 52:506-513.

Interpretive Summary: Certain fungi can infect humans and cause severe, and sometimes, fatal diseases. Such diseases are on the rise as a result of the human immune system being weakened. The weakened immune system can occur in AIDS patients, people who have received organ transplants or simply from growing old. The treatment of such diseases requires drugs that can have some fairly harmful side-effects. Moreover, it has become quite common for the fungi to become resistant to these drugs. In this study, we show how it might be possible to use safe, natural chemicals from plants to improve the effectiveness of these drugs. We call this effect "chemosensitization." It works by undermining the ability of the fungus to defend itself against the drugs. So far, we have only shown it to work under routine microbiological tests. However, if proven to work in animal models, or human clinical tests, chemosensitization could prove itself to be a new chemotherapeutic approach to lowering the amount of drug needed to be effective. This would reduce costs and the potential for unwanted side-effects. It could also result in overcoming resistance in fungi.

Technical Abstract: Candidiasis and cryptococcosis are diseases of widening global incidence as a result of increasing immunosuppressive disorders, such as AIDS. An enduring problem for treatment of these mycoses is recurrent development of resistance to introduced antifungal drugs. We examined the potential for enhancing effectiveness of antifungal drugs by chemosensitization. Several phenolic compounds were first assessed for degree of antifungal potency against nine reference strains of six species of Candida and one of Cryptococcus neoformans. The most potent chemosensitizing compounds targeted the oxidative stress response or cell wall integrity systems. Seven of 12 phenolics tested, at 5mM, showed >90% growth inhibition of all fungal strains studied. These seven were evaluated further in co-application bioassays based on a matrix of MIC levels of the test phenolic and the antifungal drugs amphotericin B, fluconazole and itraconazole. Two, thymol and 2,5-dihydroxybenzaldehyde, at sublethal doses (µM), augmented antifungal efficacy of the drugs up to 100-fold. These findings show that non-toxic natural products have potential as therapeutic chemosensitizing agents in combination with antifungal drugs. Use of such agents could lower drug dosages which would reduce cost of treatment, and harmful sequelae and overcome drug resistance.