Fungicidal synergism of fluconazole and cyclosporine in Candida albicans is not dependent on multidrug efflux transporters encoded by the CDR1, CDR2, CaMDR1, and FLU1 genes.

Détails

ID Serval
serval:BIB_C1A5CCC317C2
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Fungicidal synergism of fluconazole and cyclosporine in Candida albicans is not dependent on multidrug efflux transporters encoded by the CDR1, CDR2, CaMDR1, and FLU1 genes.
Périodique
Antimicrobial Agents and Chemotherapy
Auteur(s)
Marchetti O., Moreillon P., Entenza J.M., Vouillamoz J., Glauser M.P., Bille J., Sanglard D.
ISSN
0066-4804 (Print)
ISSN-L
0066-4804
Statut éditorial
Publié
Date de publication
2003
Volume
47
Numéro
5
Pages
1565-1570
Langue
anglais
Résumé
The combination of fluconazole (FLC) and cyclosporine (CY) is fungicidal in FLC-susceptible C. albicans (O. Marchetti, P. Moreillon, M. P. Glauser, J. Bille, and D. Sanglard, Antimicrob. Agents Chemother. 44:2373-2381, 2000). The mechanism of this synergism is unknown. CY has several cellular targets including multidrug efflux transporters. The hypothesis that CY might inhibit FLC efflux was investigated by comparing the effect of FLC-CY in FLC-susceptible parent CAF2-1 (FLC MIC, 0.25 mg/liter) and in FLC-hypersusceptible mutant DSY1024 (FLC MIC, 0.03 mg/liter), in which the CDR1, CDR2, CaMDR1, and FLU1 transporter genes have been selectively deleted. We postulated that a loss of the fungicidal effect of FLC-CY in DSY1024 would confirm the roles of these efflux pumps. Time-kill curve studies showed a more potent fungistatic effect of FLC (P = 0.05 at 48 h with an inoculum of 10(3) CFU/ml) and a more rapid fungicidal effect of FLC-CY (P = 0.05 at 24 h with an inoculum of 10(3) CFU/ml) in the FLC-hypersusceptible mutant compared to those in the parent. Rats with experimental endocarditis were treated for 2 or 5 days with high-dose FLC, high-dose CY, or both drugs combined. FLC monotherapy for 5 days was more effective against the hypersusceptible mutant than against the parent. However, the addition of CY to FLC still conferred a therapeutic advantage in animals infected with mutant DSY1024, as indicated by better survival (P = 0.04 versus the results obtained with FLC) and sterilization of valves and kidneys after a very short (2-day) treatment (P = 0.009 and 0.002, respectively, versus the results obtained with FLC). Both in vitro and in vivo experiments consistently showed that the deletion of the four membrane transporters in DSY1024 did not result in loss of the fungicidal effect of FLC-CY. Yet, the accelerated killing in the mutant suggested a "dual-hit" mechanism involving FLC hypersusceptibility due to the efflux pump elimination and fungicidal activity conferred by CY. Thus, inhibition of multidrug efflux transporters encoded by CDR1, CDR2, CaMDR1, and FLU1 genes is not responsible for the fungicidal synergism of FLC-CY. Other cellular targets must be considered.
Mots-clé
ATP-Binding Cassette Transporters/genetics, Antifungal Agents/pharmacology, Candida albicans/drug effects, Cyclosporine/pharmacology, Drug Resistance, Multiple/genetics, Drug Synergism, Drug Therapy, Combination, Endocarditis/drug therapy, Fluconazole/pharmacology, Fungal Proteins/genetics, Membrane Transport Proteins/genetics, P-Glycoprotein/genetics
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/01/2008 14:45
Dernière modification de la notice
09/05/2019 0:46
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