Reduced accumulation of drug in Candida krusei accounts for itraconazole resistance.
Due to intrinsic resistance Candida krusei is emerging as a systemic pathogen in AIDS patients undergoing fluconazole therapy, but acquired resistance to itraconazole has not been studied biochemically. We report here studies on the basis for azole resistance and sterol composition in C. krusei. An itraconazole-resistant isolate showed reduced susceptibility to azole drugs in in vitro growth inhibition studies. Accumulation of 14 alpha-methyl-3,6-diol under azole treatment was associated with growth arrest. In vitro ergosterol biosynthesis and type II binding studies suggested no alteration in the affinity to azole drugs of the target enzyme, the cytochrome P-450 sterol 14 alpha-demethylase, in the resistant isolate. Resistance was associated with a decreased intracellular content of drug in the resistant isolate.
Venkateswarlu
K
K
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, United Kingdom.
Denning
D W
DW
Manning
N J
NJ
Kelly
S L
SL
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000378:metabolism* / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D002177:Candidiasis / Q000150:complications / Q000382:microbiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004352:Drug Resistance, Microbial; D006801:Humans; D017964:Itraconazole / Q000378:metabolism* / Q000494:pharmacology*; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000096:biosynthesis
D000935:Antifungal Agents; C548418:CYP51A1 protein, human; D013261:Sterols; D017964:Itraconazole; D000666:Amphotericin B; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase