Resistant P45051A1 activity in azole antifungal tolerant Cryptococcus neoformans from AIDS patients.
Azole antifungal compounds are important in the treatment of Cryptococcosis, a major cause of mortality in AIDS patients. The target of the azole drugs is P450 mediated sterol 14 alpha-demethylase. We have investigated the P450 system of Cryptococcus neoformans with respect to azole tolerance observed in clinical isolates which were obtained following the failure of fluconazole therapy. The clinical failure was correlated with in vitro tolerance of azole antifungal when compared to wild-type strains. The microsomal P450 system was typical of yeast and fungi and fluconazole tolerance was not associated with defective sterol biosynthesis. The strains had slightly elevated P450 content and slightly reduced azole levels in the cells, but a clear cause for resistance was the increased level of drug needed to inhibit the sterol 14 alpha-demethylase in vitro.
Lamb
D C
DC
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, Sheffield University, UK.
Corran
A
A
Baldwin
B C
BC
Kwon-Chung
J
J
Kelly
S L
SL
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000382:microbiology*; D003453:Cryptococcosis / Q000188:drug therapy / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004352:Drug Resistance, Microbial; D004361:Drug Tolerance; D004875:Ergosterol / Q000096:biosynthesis; D015725:Fluconazole / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008861:Microsomes / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000032:analysis; D017211:Treatment Failure
C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D013261:Sterols; D017964:Itraconazole; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D007654:Ketoconazole; D004875:Ergosterol