MOLECULAR AND GENETIC APPROACHES TO SUPPRESSING FUNGAL PATHOGENS AND MYCOTOXIN CONTAMINATION
Location: Plant Mycotoxin Research
Title: Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents
Submitted to: Fungal Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 6, 2010
Publication Date: October 6, 2010
Citation: Kim, J.H., Campbell, B.C., Mahoney, N.E., Chan, K.L., Molyneux, R.J., Balajee, A. 2010. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents. Fungal Biology. 114:817-824.
Interpretive Summary: Certain types of fungi can cause serious diseases of humans. One group of fungi called aspergilli can infect the human lung and spread to other organs of the body. This disease is aspergillosis, and is mainly a problem of people who live in agrarian places. The disease is highly invasive and incapacitating, and frequently fatal. In order to combat this disease, doctors often prescribe certain drugs. However, these drugs, in themselves, have a number of unpleasant side-effects and can make the patient feel quite sick. ARS scientists, in partnership with a scientist from the CDC, have developed a way of making these antifungal drugs more effective while also lowering the dose. The new technique is called chemosensitization, where small amounts of a safe natural compound are used to disrupt the ability of the fungi to respond protectively to drug treatment. This finding could have a major impact on how patients are treated for aspergillosis and other fungal diseases.
Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl or chloro group at position 4 of the aromatic ring, or by esterification of the carboxylic acid with an alkyl group, respectively. Thymol, a natural phenolic compound, was a potent chemosensitizing agent when co-applied with the antifungal drugs fluconazole and ketoconazole. The thymol-azole drug combination achieved complete inhibition of fungal growth at dosages 1000 times lower than the drugs, alone. Co-applications of thymol with selected benzo analogs also resulted in chemosensitization, wherein fungal growth was completely inhibited at lower dosages. Use of two mitogen-activated protein kinase (MAPK) mutants of A. fumigatus, sakA' and mpkC', having deleted genes in the oxidative stress response pathway, indicated antifungal and/or chemosensitization activity of the benzo analogs was by disruption of oxidative stress response. The results showed both these genes play overlapping roles in the MAPK system in this fungus. The potential of safe, natural compounds to serve as chemosensitizing agents to augment efficacy of commercial antifungal agents is discussed.