title: Mode of action and resistance to azole antifungals associated with the formation of 14 alpha-methylergosta-8,24(28)-dien-3 beta,6 alpha-diol.
abstract: Azole antifungal compounds inhibit sterol 14 alpha-demethylase. They are used extensively for the treatment of immunocompromised patients where fungal infection is common and often results in death. Resistance to the compounds is emerging, particularly in fungal pathogens obtained from AIDS patients undergoing prolonged therapy. We show here that cell growth arrest correlates with the accumulation of 14 alpha-methyl-ergosta-8,24(28)-dien-3 beta,6 alpha-diol in a yeast strain with a sterol 14 alpha-demethylase gene disruption, which mimics stringent treatment conditions. Cells can overcome the effect of such a block by a suppressor mutation in sterol delta 5,6 desaturation and acquire azole resistance. Plasmid-based complementation of sterol 14 alpha-demethylase defect does not alter the azole susceptibility of strains containing these suppressor mutations, showing resistance is due entirely to the delta 5.6 desaturase defect.
authors.affiliation: Krebs Institute for Biomolecular Research, Department of Molecular Biology, University of Sheffield, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Kelly
authors.forename: D C
authors.initials: DC
authors.lastname: Lamb
authors.forename: A J
authors.initials: AJ
authors.lastname: Corran
authors.forename: B C
authors.initials: BC
authors.lastname: Baldwin
authors.forename: D E
authors.initials: DE
authors.lastname: Kelly
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004351:Drug Resistance; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000378:metabolism; D005816:Genetic Complementation Test; D009154:Mutation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000378:metabolism; D013489:Suppression, Genetic
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D013261:Sterols; C059675:14-methylergosta-8,24(28)-dien-3,6-diol; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; C039306:sterol delta-5 desaturase; D004875:Ergosterol