Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs.
Authors:
Kim, J. Mahoney, N. Chan, K. Molyneux, R. May, G. USDA, ARS
Source:
Biochemical and biophysical research communications. 2008 July 18, v. 372, issue 1, p. 266-271.
NALT Subjects:
mycoses Aspergillus fumigatus animal pathogenic fungi drug resistance cell walls mitogen-activated protein kinase protein kinase C signal transduction microbial physiology antifungal agents human health
Other Subjects:
2,3-dihydroxybenzaldehyde
Issue Date:
18-Jul-2008
Abstract:
Tolerance of human pathogenic fungi to antifungal drugs is an emerging medical problem. We show how strains of the causative agent of human aspergillosis, Aspergillus fumigatus, tolerant to cell wall-interfering antimycotic drugs become susceptible through chemosensitization by natural compounds. Tolerance of the A. fumigatus mitogen-activated protein kinase (MAPK) mutant, sakAΔ, to these drugs indicates the osmotic/oxidative stress MAPK pathway is involved in maintaining cell wall integrity. Using deletion mutants of the yeast, Saccharomyces cerevisiae, we first identified thymol and 2,3-dihydroxybenzaldehyde (2,3-D) as potent chemosensitizing agents that target the cell wall. We then used these chemosensitizing agents to act as synergists to commercial antifungal drugs against tolerant strains of A. fumigatus. Thymol was an especially potent chemosensitizing agent for amphotericin B, fluconazole or ketoconazole. The potential use of natural, safe chemosensitizing agents in antifungal chemotherapy of human mycoses as an alternative to combination therapy is discussed.
