Resistance to fluconazole in Candida albicans from AIDS patients correlated with reduced intracellular accumulation of drug.
Mucosal candidosis is an almost inevitable consequence of AIDS. Resistance to fluconazole therapy associated with enhanced tolerance, detectable in microbiological estimation of sensitivity, occurs in up to 10% of cases with late-stage AIDS. We report here our biochemical analysis of the basis of resistance in a study of two susceptible and two resistant isolates. Resistance was not associated with a change in the target enzyme sterol 14 alpha-demethylase, as indicated by equivalent levels of fluconazole inhibition of activity in extracts from all four isolates, or by mutations in sterol delta desaturase as previously observed in Saccharomyces cerevisiae and Ustilago maydis. Reduced cellular content of fluconazole in the resistant isolates of between six to ten-fold was observed which could account for their resistant phenotype.
Venkateswarlu
K
K
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, Sheffield University, UK.
Denning
D W
DW
Manning
N J
NJ
Kelly
S L
SL
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000382:microbiology*; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D002178:Candidiasis, Chronic Mucocutaneous / Q000188:drug therapy / Q000382:microbiology*; D002775:Cholestadienols / Q000032:analysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004352:Drug Resistance, Microbial; D004875:Ergosterol / Q000032:analysis; D015725:Fluconazole / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007810:Lanosterol / Q000031:analogs & derivatives / Q000032:analysis; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000378:metabolism; D058886:Sterol 14-Demethylase
D000935:Antifungal Agents; C548418:CYP51A1 protein, human; D002775:Cholestadienols; D007810:Lanosterol; C008693:obtusifoliol; C014520:ebericol; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; C039306:sterol delta-5 desaturase; D004875:Ergosterol