Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol delta5,6-desaturation.
Fluconazole resistance occurs in > 10% of cases of candidosis during the late stages of AIDS. We show here in two clinical isolates that resistance was caused by defective sterol delta5,6-desaturation. This altered the type of sterol accumulating under fluconazole treatment from 14alpha-methylergosta-8,24(28)-dien-3beta,6alpha -diol to 14alpha-methylfecosterol which is capable of supporting growth. A consequence of this mechanism of azole resistance is that an absence of ergosterol causes cross-resistance to the other major antifungal agent available, amphotericin B. The results also show that growth arrest after fluconazole treatment of C. albicans in clinical conditions is caused by 14alpha-methylergosta-8,24(28)-dien-3beta,6alpha -diol accumulation.
Kelly
S L
SL
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, Sheffield University, UK. S.Kelly@Sheffield.ac.uk
Lamb
D C
DC
Kelly
D E
DE
Manning
N J
NJ
Loeffler
J
J
Hebart
H
H
Schumacher
U
U
Einsele
H
H
D000163:Acquired Immunodeficiency Syndrome / Q000382:microbiology*; D000328:Adult; D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D004352:Drug Resistance, Microbial; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010088:Oxidoreductases / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*
D000935:Antifungal Agents; D013261:Sterols; D000666:Amphotericin B; D015725:Fluconazole; D010088:Oxidoreductases; C039306:sterol delta-5 desaturase