Submitted to: Frontiers in Microbiology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/1/2012
Publication Date: 3/16/2012
Citation: Kim, J.H., Chan, K.L., Faria, N.G., Campbell, B.C. 2012. Targeting the oxidative stress response system of fungi with safe, redox-potent chemosensitizing agents. Frontiers in Microbiology. 3:88. Interpretive Summary: Many of the currently available drugs for treating fungal infections of humans are toxic to the fungus through oxidation. They function on a biological basis somewhat similar to that of “rusting” of metals, but only much more quickly. Fungi have evolved a genetic network to protect themselves from this oxidation, and as a result have developed resistance to those drugs that kill the fungus by this route. This paper describes what genes of the fungus are involved in this protection and how this protection can be circumvented. The circumvention can be done by using certain natural compounds that destabilize the protective network of the fungus and actually contribute additional oxidative stress to the fungus to that of the antifungal drug. As a result, resistance can be overcome and the fungus can be killed using a lesser amount of the antifungal drug than usual. This is important because if found to work on a clinical basis, it would reduce the cost of treatments and the level of negative side effects of drug usage.
Technical Abstract: One mode of action of the antimycotics amphotericin B (AMB) or itraconazole (ITZ) against filamentous fungi involves cellular oxidative stress response. Aspergillus fumigatus sakA', a mitogen-activated protein kinase (MAPK) gene deletion mutant in the antioxidation system, was more sensitive to AMB or ITZ compared to A. fumigatus strains AF293 (wild type) and mpkC' (a MAPK gene deletion mutant, in polyalcohol sugar utilization system). The sakA' mutant showed no growth at 0.5 'g mL-1 of ITZ or a reduced growth at 1.0 to 2.0 'g mL-1 of AMB in agar bioassay, while the other strains exhibited more robust growth than the sakA' mutant. Also, over 99.9% of fungicidality was achieved in the sakA' mutant at dosage levels of ITZ or AMB lower than that for the other strains in microdilution bioassays. Results further indicated that, although SakA and MpkC seemed to play overlapping roles under organic peroxide (t-BuOOH)- or hydrogen peroxide (H2O2)-mediated oxidative stress, it was mainly the SakA signalling pathway that was responsible for fungal tolerance/response to AMB - or ITZ-triggered toxicity in Aspergillus. In addition, our data suggested that Aspergillus msnA, an ortholog of the Saccharomyces cerevisiae MSN2 gene that encodes a stress-responsive C2H2-type zinc-finger regulator, and sakA and/or mpkC (upstream MAPKs) are located in the same stress response network under the t-BuOOH-, H2O2- or AMB-triggered toxicity. Of note is that ITZ sensitive yeast pathogens (Candida krusei 6258, Cryptococcus neoformans CN24) were also sensitive to t-BuOOH, indicating the correlation between ITZ toxicity and fungal oxidative stress response. Redox-potent natural compounds, i.e., 2,3-dihydroxybenzaldehyde (2,3-DHBA), thymol (THY) or salicylaldehyde (SA), enhanced the activity of AMB or ITZ, when co-applied. Thus, redox-potent compounds, which target the antioxidation system in fungi, possess potent chemosensitizing capacity to enhance efficacy of conventional oxidative stress drugs. Such chemosensitization can reduce costs and alleviate negative side effects associated with current antifungal treatments.