Synergic effects of tactolimus and azole antifungal agents against azole-resistant Candida albican strains.

We investigated the effects of combining tacrolimus and azole antifungal agents in azole-resistant strains of Candida albicans by comparing the accumulation of [3H]itraconazole. The CDR1-expressing resistant strain C26 accumulated less itraconazole than the CaMDR-expressing resistant strain C40 or the azole-sensitive strain B2630. A CDR1-expressing Saccharomyces cerevisiae mutant, DSY415, showed a marked reduction in the accumulation of both fluconazole and itraconazole. A CaMDR-expressing S. cerevisiae mutant, DSY416, also showed lower accumulation of fluconazole, but not of itraconazole. The addition of sodium azide, an electron-transport chain inhibitor, increased the intracellular accumulation of itraconazole only in the C26 strain, and not in the C40 or B2630 strains. Addition of tacrolimus, an inhibitor of multidrug resistance proteins, resulted in the highest increase in itraconazole accumulation in the C26 strain. The combination of itraconazole and tacrolimus was synergic in azole-resistant C. albicans strains. In the C26 strain, the MIC of itraconazole decreased from >8 to 0.5 mg/L when combined with tacrolimus. Our results showed that two multidrug resistance phenotypes (encoded by the CDR1 and CaMDR genes) in C. albicans have different substrate specificity for azole antifungal agents and that a combination of tacrolimus and azole antifungal agents is effective against azole-resistant strains of C. albicans.

[1]  T. C. White,et al.  The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14alpha demethylase in Candida albicans , 1997, Antimicrobial agents and chemotherapy.

[2]  Brian C. Baldwin,et al.  The Mutation T315A in Candida albicans Sterol 14α-Demethylase Causes Reduced Enzyme Activity and Fluconazole Resistance through Reduced Affinity* , 1997, The Journal of Biological Chemistry.

[3]  J. Martínez-Suárez,et al.  Patterns of fluconazole susceptibility in isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis due to Candida albicans. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  R. Cannon,et al.  Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance , 1996, Antimicrobial agents and chemotherapy.

[5]  H. Nakagawa,et al.  Tacrolimus Has Antifungal Activities against Malassezia furfur Isolated from Healthy Adults and Patients with Atopic Dermatitis , 1996 .

[6]  D. Sanglard,et al.  Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors , 1996, Antimicrobial agents and chemotherapy.

[7]  W. Dalton,et al.  Resistance to the chemosensitizer verapamil in a multi‐drug‐resistant (MDR) human multiple myeloma cell line , 1996, International journal of cancer.

[8]  R. Collins,et al.  FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation. , 1996, Blood.

[9]  W T Bellamy,et al.  P-glycoproteins and multidrug resistance. , 1996, Annual review of pharmacology and toxicology.

[10]  K. Kuchler,et al.  Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters , 1995, Antimicrobial agents and chemotherapy.

[11]  B. Althaus,et al.  Antifungal Prophylaxis in Bone Marrow Transplant , 1995, The Annals of pharmacotherapy.

[12]  P. Marichal,et al.  Origin of differences in susceptibility of Candida krusei to azole antifungal agents , 1995, Mycoses.

[13]  A. Oppenheim,et al.  Multidrug resistance in Candida albicans: disruption of the BENr gene , 1995, Antimicrobial agents and chemotherapy.

[14]  P. Marichal,et al.  Mechanisms of resistance to azole antifungals. , 1995, Acta biochimica Polonica.

[15]  F. Odds,et al.  Molecular mechanisms of drug resistance in fungi. , 1994, Trends in microbiology.

[16]  P. Rathod,et al.  Loss of function mutation in the yeast multiple drug resistance gene PDR5 causes a reduction in chloramphenicol efflux , 1994, Antimicrobial Agents and Chemotherapy.

[17]  J. Ordonez,et al.  Enhancement of daunorubicin accumulation, retention, and cytotoxicity by verapamil or cyclosporin A in blast cells from patients with previously untreated acute myeloid leukemia. , 1993, Blood.

[18]  Y. Tanigawara,et al.  Human P-glycoprotein transports cyclosporin A and FK506. , 1993, The Journal of biological chemistry.

[19]  I. Pastan,et al.  Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[20]  B. Bierer,et al.  Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype. , 1992, Blood.

[21]  J. Lankelma,et al.  Induction by verapamil of a rapid increase in ATP consumption in multidrug‐resistant tumor cells , 1988, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.