       Document 0793
 DOCN  M9650793
 TI    Mechanisms of resistance to azole antifungal agents in Candida albicans
       isolates from AIDS patients involve specific multidrug transporters.
 DT    9605
 AU    Sanglard D; Kuchler K; Ischer F; Pagani JL; Monod M; Bille J; Institut
       de Microbiologie, Centre Hospitalier Universitaire; Vaudois, Lausanne,
       Switzerland.
 SO    Antimicrob Agents Chemother. 1995 Nov;39(11):2378-86. Unique Identifier
       : AIDSLINE GENBANK/X53823
 AB    Azole antifungal agents, and especially fluconazole, have been used
       widely to treat oropharyngeal candidiasis in patients with AIDS. An
       increasing number of cases of clinical resistance against fluconazole,
       often correlating with in vitro resistance, have been reported. To
       investigate the mechanisms of resistance toward azole antifungal agents
       at the molecular level in clinical C. albicans isolates, we focused on
       resistance mechanisms related to the cellular target of azoles, i.e.,
       cytochrome P450(14DM) (14DM) and those regulating the transport or
       accumulation of fluconazole. The analysis of sequential isogenic C.
       albicans isolates with increasing levels of resistance to fluconazole
       from five AIDS patients showed that overexpression of the gene encoding
       14DM either by gene amplification or by gene deregulation was not the
       major cause of resistance among these clinical isolates. We found,
       however, that fluconazole-resistant C. albicans isolates failed to
       accumulate 3H-labelled fluconazole. This phenomenon was reversed in
       resistant cells by inhibiting the cellular energy supply with azide,
       suggesting that resistance could be mediated by energy-requiring efflux
       pumps such as those described as ATP-binding cassette (ABC) multidrug
       transporters. In fact, some but not all fluconazole-resistant clinical
       C. albicans isolates exhibited up to a 10-fold relative increase in mRNA
       levels for a recently cloned ABC transporter gene called CDR1. In an
       azole-resistant C. albicans isolate not overexpressing CDR1, the gene
       for another efflux pump named BENr was massively overexpressed. This
       gene was cloned from C. albicans for conferring benomyl resistance in
       Saccharomyces cerevisiae. Therefore, at least the overexpression or the
       deregulation of these two genes potentially mediates resistance to
       azoles in C. albicans clinical isolates from AIDS patients with
       oropharyngeal candidiasis. Involvement of ABC transporters in azole
       resistance was further evidenced with S. cerevisiae mutants lacking
       specific multidrug transporters which were rendered hypersusceptible to
       azole derivatives including fluconazole, itraconazole, and ketoconazole.
 DE    Antifungal Agents/METABOLISM/*PHARMACOLOGY
       Azoles/METABOLISM/*PHARMACOLOGY  ABC Transporters/GENETICS/METABOLISM
       AIDS-Related Opportunistic Infections/*MICROBIOLOGY  Base Sequence
       Blotting, Northern  Candida albicans/*DRUG EFFECTS/GENETICS/METABOLISM
       Candidiasis, Oral/*MICROBIOLOGY  Drug Resistance, Microbial/GENETICS
       Drug Resistance, Multiple/GENETICS  DNA, Fungal/METABOLISM
       Fluconazole/METABOLISM/PHARMACOLOGY  Fungal Proteins/GENETICS  Genes,
       Fungal  Human  Microbial Sensitivity Tests  Molecular Sequence Data
       Nucleic Acid Hybridization  P-Glycoprotein/GENETICS/*METABOLISM
       Plasmids  Polymerase Chain Reaction  RNA, Fungal/METABOLISM
       Saccharomyces cerevisiae/GENETICS/METABOLISM  Support, Non-U.S. Gov't
       JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

