Mechanism of action of coumarin and silver(I)-coumarin complexes against the pathogenic yeast Candida albicans.
The anti-fungal activity and mode of action of a range of silver(I)-coumarin complexes was examined. The most potent silver(I)-coumarin complexes, namely 7-hydroxycoumarin-3-carboxylatosilver(I), 6-hydroxycoumarin-3-carboxylatosilver(I) and 4-oxy-3-nitrocoumarinbis(1,10-phenanthroline)silver(I), had MIC80 values of between 69.1 and 4.6 microM against the pathogenic yeast Candida albicans. These compounds also reduced respiration, lowered the ergosterol content of cells and increased the trans-membrane leakage of amino acids. A number of the complexes disrupted cytochrome synthesis in the cell and induced the appearance of morphological features consistent with cell death by apoptosis. These compounds appear to act by disrupting the synthesis of cytochromes which directly affects the cell's ability to respire. A reduction in respiration leads to a depletion in ergosterol biosynthesis and a consequent disruption of the integrity of the cell membrane. Disruption of cytochrome biosynthesis may induce the onset of apoptosis which has been shown previously to be triggered by alteration in the location of cytochrome c. Silver(I)-coumarin complexes demonstrate good anti-fungal activity and manifest a mode of action distinct to that of the conventional azole and polyene drugs thus raising the possibility of their use when resistance to conventional drug has emerged or in combination with such drugs.
Thati
Bhumika
B
Medical Mycology Unit, National Institute for Cellular Biotechnology, Department of Biology, National University of Ireland Maynooth, Co. Kildare, Ireland.
Noble
Andy
A
Rowan
Raymond
R
Creaven
Bernadette S
BS
Walsh
Maureen
M
McCann
Malachy
M
Egan
Denise
D
Kavanagh
Kevin
K
D000935:Antifungal Agents; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003580:Cytochromes / Q000378:metabolism; D004271:DNA, Fungal / Q000302:isolation & purification; D004875:Ergosterol / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008854:Microscopy, Electron; D010101:Oxygen Consumption / Q000187:drug effects; D018030:Silver Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000935:Antifungal Agents; D003374:Coumarins; D003580:Cytochromes; D004271:DNA, Fungal; D018030:Silver Compounds; D004875:Ergosterol