Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors

Détails

ID Serval
serval:BIB_9C1896458842
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors
Périodique
Antimicrobial Agents and Chemotherapy
Auteur⸱e⸱s
Sanglard  D., Ischer  F., Monod  M., Bille  J.
ISSN
0066-4804 (Print)
Statut éditorial
Publié
Date de publication
10/1996
Volume
40
Numéro
10
Pages
2300-5
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Oct
Résumé
Some Candida albicans isolates from AIDS patients with oropharyngeal candidiasis are becoming resistant to the azole antifungal agent fluconazole after prolonged treatment with this compound. Most of the C. albicans isolates resistant to fluconazole fail to accumulate this antifungal agent, and this has been considered a cause of resistance. This phenomenon was shown to be linked to an increase in the amounts of mRNA of a C. albicans ABC (ATP-binding cassette) transporter gene called CDR1 and of a gene conferring benomyl resistance (BENr), the product of which belongs to the class of major facilitator multidrug efflux transporters (D. Sanglard, K. Kuchler, F. Ischer, J. L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother. 39:2378-2386, 1995). To analyze the roles of these multidrug transporters in the efflux of azole antifungal agents, we constructed C. albicans mutants with single and double deletion mutations of the corresponding genes. The mutants were tested for their susceptibilities to these antifungal agents. Our results indicated that the delta cdr1 C. albicans mutant was hypersusceptible to the azole derivatives fluconazole, itraconazole, and ketoconazole, thus showing that the ABC transporter Cdr1 can use these compounds as substrates. The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine). The same mutant was slightly more susceptible than the wild type to nocodazole, cerulenin, and crystal violet but not to amphotericin B, nikkomycin Z, flucytosine, or pradimicin. In contrast, the delta ben mutant was rendered more susceptible only to the mutagen 4-nitroquinoline-N-oxide. However, this mutation increased the susceptibilities of the cells to cycloheximide and cerulenin when the mutation was constructed in a delta cdr1 background. The assay used in the present study could be implemented with new antifungal agents and is a powerful tool for assigning these substances as putative substrates of multidrug transporters.
Mots-clé
ATP-Binding Cassette Transporters/genetics/metabolism Antifungal Agents/*pharmacology Antimetabolites/*pharmacology Azoles/pharmacology Candida albicans/*drug effects/*genetics/metabolism Culture Media Drug Resistance, Microbial Genes, Fungal Microbial Sensitivity Tests Molecular Sequence Data Mutation P-Glycoprotein/*genetics/*metabolism Polymerase Chain Reaction Transformation, Genetic
Pubmed
Web of science
Création de la notice
25/01/2008 17:47
Dernière modification de la notice
20/08/2019 16:02
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