Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs.
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.
Kim
Jong
J
Plant Mycotoxin Research Unit, Western Regional Research Center, USDA-ARS, 800 Buchanan Street, Albany, CA 94710, USA.
Campbell
Bruce
B
Mahoney
Noreen
N
Chan
Kathleen
K
Molyneux
Russell
R
May
Gregory
G
D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001228:Aspergillosis / Q000382:microbiology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics; D001547:Benzaldehydes / Q000302:isolation & purification / Q000494:pharmacology*; D002396:Catechols / Q000302:isolation & purification / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D002473:Cell Wall / Q000187:drug effects; D025141:Drug Resistance, Fungal / Q000187:drug effects* / Q000235:genetics; D015725:Fluconazole / Q000494:pharmacology; D017353:Gene Deletion; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D018384:Oxidative Stress; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013012:Sorbitol / Q000494:pharmacology; D013943:Thymol / Q000302:isolation & purification / Q000494:pharmacology*
D000935:Antifungal Agents; D001547:Benzaldehydes; D002396:Catechols; D029701:Saccharomyces cerevisiae Proteins; C067077:2,3-dihydroxybenzaldehyde; D013943:Thymol; D013012:Sorbitol; D000666:Amphotericin B; D015725:Fluconazole; C072075:BCK1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; C072724:SLT2 protein, S cerevisiae; D020929:Mitogen-Activated Protein Kinase Kinases; D007654:Ketoconazole