Submitted to: Annals of Clinical Microbiology and Antimicrobials
Publication Type: Peer reviewed journal
Publication Acceptance Date: 5/6/2011
Publication Date: 5/31/2011
Citation: Kim, J.H., Chan, K.L., Mahoney, N.E., Campbell, B.C. 2011. Antifungal activity of redox-active benzaldehydes that target cellular antioxidation. Annals of Clinical Microbiology and Antimicrobials. 10:23.DOI:10.1186/1476-0711-10-23. Interpretive Summary: Serious fungal diseases of humans are on the increase, worldwide. This is mainly a result of the increase in incidence of immunocompromised patients, such as those suffering from AIDS. Because of these patients being weak in responding to fungal infections, they have had to be heavily treated with antifungal drugs. One of the results of this widespread treatment is the major emerging problem of pathogenic fungi becoming resistant to these drugs. Moreover, antifungal drugs have many negative side effects. This research shows that using safe, natural compounds called benzaldehydes can improve the effectiveness of antifungal drugs. These compounds are used to attack vulnerabilities in the fungus, making them weaker to the drugs. The results are loss of resistance and the lowering of doses so that the negative side effects of the drugs are not so dramatic.
Technical Abstract: Many pathogenic fungi are becoming resistant to currently available drugs. Disruption of cellular antioxidation systems should be an effective method for control of fungal pathogens. Such disruption can be achieved with redox-active compounds. The aim of this study was to identify benzaldehydes that disrupt the fungal antioxidation system. These compounds could then function as chemosensitizing agents in concert with conventional drugs or fungicides to improve antifungal efficacy. Several benzaldehydes are identified having potent antifungal activity. Structure-activity analysis reveals that antifungal activity increases by the presence of an ortho-hydroxyl group in the aromatic ring. Certain benzaldehydes, in combination with phenylpyrroles, overcome tolerance of A. fumigatus MAPK mutants to this agent and/or increase sensitivity of fungal pathogens to mitochondrial respiration inhibitory agents. Thus, natural benzaldehydes targeting cellular antioxidation components of fungi, such as superoxide dismutases, glutathione reductase, etc., effectively inhibit fungal growth. They possess antifungal or chemosensitizing capacity to enhance efficacy of conventional antifungal agents, reducing costs, abating resistance, and alleviating negative side effects associated with current antifungal treatments.