MOLECULAR AND GENETIC APPROACHES TO SUPPRESSING FUNGAL PATHOGENS AND MYCOTOXIN CONTAMINATION
Location: Plant Mycotoxin Research
Title: Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs
Submitted to: Biochemical and Biophysical Research Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 16, 2008
Publication Date: July 18, 2008
Citation: Kim, J.H., Campbell, B.C., Mahoney, N.E., Chan, K.L., Molyneux, R.J., May, G. 2008. Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs. Biochemical and Biophysical Research Communications.372(1):266-271.
Interpretive Summary: Certain fungi can cause serious diseases of humans. These fungi can infect internal organs, especially the lungs. People that are most prone to these types of infections have weakened immune systems. The most common types of people with weakened systems include the aged, patients given immunosuppressive agents for organ transplants, those undergoing chemotherapy for cancer and those suffering from AIDS. Aspergillus fumigatus is the number one agent that causes aspergillosis, a serious infectious disease that can spread of the lungs to other organs, including the liver, kidneys and the brain. Drugs used to treat aspergillosis are highly toxic, themselves, and fungi invariably develop resistance. Resistance to these drugs is a huge medical problem. USDA scientists have discovered an approach called "chemosensitization" where safe natural products can be used to weaken drug resistant fungi and render them susceptible to drugs to which they were previously resistant.
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, sakAdelta, 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.