Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters


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Article: article from journal or magazin.
Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters
Antimicrobial Agents and Chemotherapy
Sanglard  D., Kuchler  K., Ischer  F., Pagani  J. L., Monod  M., Bille  J.
0066-4804 (Print)
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Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Nov
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.
AIDS-Related Opportunistic Infections/*microbiology ATP-Binding Cassette Transporters/genetics/metabolism Antifungal Agents/metabolism/*pharmacology Azoles/metabolism/*pharmacology Base Sequence Blotting, Northern Candida albicans/*drug effects/genetics/metabolism Candidiasis, Oral/*microbiology DNA, Fungal/metabolism Drug Resistance, Microbial/genetics Drug Resistance, Multiple/genetics Fluconazole/metabolism/pharmacology Fungal Proteins/genetics Genes, Fungal Humans *Membrane Transport Proteins Microbial Sensitivity Tests Molecular Sequence Data Nucleic Acid Hybridization P-Glycoprotein/genetics/*metabolism Plasmids Polymerase Chain Reaction RNA, Fungal/metabolism Saccharomyces cerevisiae/genetics/metabolism
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25/01/2008 16:46
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20/08/2019 14:34
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