Submitted to: Frontiers in Microbiology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 6/21/2012
Publication Date: 7/17/2012
Citation: Kim, J.H., Faria, N.C., Martins, M., Chan, K.L., Campbell, B.C. 2012. Enhancement of antimycotic activity of amphotericin B by targeting the oxidative stress response of Candida and Cryptococcus with natural dihydroxybenzaldehydes. Frontiers in Microbiology. 3:261. DOI:10.3389/fmicb2012.00261 Interpretive Summary: Patients suffering from HIV infection (AIDS) commonly die as a result of fungal infections caused by yeasts. Treatment of AIDS patients with antifungal drugs over the past few decades has resulted in the emergence of many new strains of yeasts that are resistant to currently available drugs. We report, here, how certain natural compounds called benzaldehydes can weaken the yeasts so that they can no longer resist one of the most highly used drugs for treating yeast infections, amphotericin B. The natural compounds disrupt the ability of the yeast to combat certain stresses that are exerted by the drug. The results of this research indicate a potential of using safe, natural compounds to improve the efficacy of antifungal drugs.
Technical Abstract: Many yeast pathogens of humans have become resistant to currently available drugs. Certain types of compounds can increase efficacy of antimycotic drugs through a process termed chemosensitization. Chemosensitizing efficacy was determined in Candida albicans, C. krusei, C. tropicalis and Cryptococcus neoformans, yeasts that are causative agents of human candidasis or cryptococcosis. We compared chemosensitizing activities of four redox-active benzaldehydes, i.e., two dihydroxybenzaldehydes (DHBAs) [2,3-dihydroxybenzaldehyde (2,3-DHBA), 2,5-dihydroxybenzaldehyde (2,5-DHBA)] and two nonhydroxylated benzaldehydes (non-DHBAs) [trans-cinnamaldehyde, 3,5-dimethoxybenzaldehyde (3,5-DMBA)], to the preferred commercial drug for treating these diseases, amphotericin B (AMB). In most yeast pathogens tested, co-application of either of the DHBAs enhanced antifungal activity of AMB, as measured by lower minimum inhibitory concentrations (MICs) and/or minimum fungicidal concentrations (MFCs). With non-DHBAs, certain levels of chemosensitizing activity were detected with cinnamaldehyde (for MFCs). However, no chemosensitization was achieved by 3,5-DMBA in any of the yeasts tested. This lack of chemosensitization was mainly due to hypertolerance of yeast strains to 3,5-DMBA. Results show certain DHBAs are potent chemosensitizing agents to AMB in Candida and Cryptococcus. 2,3-DHBA showed higher antifungal activity than 2,5-DHBA (i.e., structure-activity relationship). Also, the two DHBAs possessed much higher chemosensitizing potency than the non-DHBAs tested. DHBAs may exert their chemosensitizing activity to AMB by targeting mitochondrial superoxide dismutase (Mn-SOD). DHBAs could serve as effective chemosensitizers to AMB for improved chemotherapeutic treatment of candidiasis and cryptococcosis.