ARS | Publication request: 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 29, 2010
Publication Date: N/A

Interpretive Summary: There are many serious fungal diseases that infect our internal tissues and organs. These types of fungal infections are very difficult to treat. Two major problems involve resistance of these fungal pathogens to drug treatment and the fact that no new fungal drugs appear to be available in the near future. PMR scientists have discovered a new method that may weaken fungal pathogens so that they become more susceptible to antifungal drugs. This is done by using safe, natural chemical compounds that disrupt the ability of the fungus to respond to stress, such as exposure to drugs. This "chemosensitization" may serve as a new therapeutic tool to fight fungal diseases and result in elevating the activity of currently available drugs, reduce the dosage required, thus reducing costs and the potential for harmful side-effects.

Technical Abstract: Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a 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 azole drugs fluconazole and ketoconazole. Co-application of thymol with amphotericin B produced a chemosensitizing effect on all strains of aspergilli tested except for two of three strains of A. terreus. In these latter cases there was an opposing antagonistic effect. Use of two mitogen-activated protein kinase (MAPK) mutants of A. fumigatus, sakA' and mpkC', indicated chemosensitization activity of the benzo analogues was by disruption of oxidative stress response. Safe, natural compounds or analogues may serve as chemosensitizing agents to enhance efficacy of commercial antifungal agents.