TY - JOUR
T1 - Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs
AU - Kim, Jong
AU - Campbell, Bruce
AU - Mahoney, Noreen
AU - Chan, Kathleen
AU - Molyneux, Russell
AU - May, Gregory
N1 - Funding Information:
This research was conducted under USDA-ARS CRIS Project 5325-42000-035-00D and Washington Tree Fruit Research Commission Project # CP-07-701.
PY - 2008/7/18
Y1 - 2008/7/18
N2 - 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.
AB - 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.
KW - Antifungal chemotherapy
KW - Aspergillus fumigatus
KW - Chemosensitization
KW - Combination therapy
KW - MAPK
KW - Natural compounds
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U2 - 10.1016/j.bbrc.2008.05.030
DO - 10.1016/j.bbrc.2008.05.030
M3 - Article
C2 - 18486603
AN - SCOPUS:46349095613
SN - 0006-291X
VL - 372
SP - 266
EP - 271
JO - Biochemical and biophysical research communications
JF - Biochemical and biophysical research communications
IS - 1
ER -