Overexpression of Candida Albicans CDR1, CDR2, or MDR1 Does Not Produce Significant Changes in Echinocandin Susceptibility

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2006 Mar 30

PMID 16569823

Citations 56

Authors

K Niimi

K Maki

F Ikeda

A R Holmes

E Lamping

M Niimi

B C Monk

R D Cannon

Affiliations

Soon will be listed here.

Abstract

The micafungin and caspofungin susceptibilities of Candida albicans laboratory and clinical isolates and of Saccharomyces cerevisiae strains stably hyperexpressing fungal ATP-binding cassette (ABC) or major facilitator superfamily (MFS) transporters involved in azole resistance were determined using three separate methods. Yeast strains hyperexpressing individual alleles of ABC transporters or an MFS transporter from C. albicans gave the expected resistance profiles for the azoles fluconazole, itraconazole, and voriconazole. The strains hyperexpressing CDR2 showed slightly decreased susceptibility to caspofungin in agar plate drug resistance assays, as previously reported, but increased susceptibility to micafungin compared with either the strains hyperexpressing CDR1 or the null parent deleted of seven ABC transporters. The strains hyperexpressing CDR1 showed slightly decreased susceptibility to micafungin in these assays. A C. albicans clinical isolate overexpressing both Cdr1p and Cdr2p relative to its azole-sensitive isogenic progenitor acquired resistance to azole drugs and showed reduced susceptibility to caspofungin and slightly increased susceptibility to micafungin in agar plate drug resistance assays. None of the strains showed significant resistance to micafungin or caspofungin in liquid microdilution susceptibility assays. The antifungal activities of micafungin and caspofungin were similar in agarose diffusion assays, although the shape and size of the caspofungin inhibitory zones were affected by medium composition. The assessment of micafungin and caspofungin potency is therefore assay dependent; the differences seen with agar plate drug resistance assays occur over narrow ranges of echinocandin concentrations and are not of clinical significance.

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References

Moudgal V, Little T, Boikov D, Vazquez J . Multiechinocandin- and multiazole-resistant Candida parapsilosis isolates serially obtained during therapy for prosthetic valve endocarditis. Antimicrob Agents Chemother. 2005; 49(2):767-9. PMC: 547225. DOI: 10.1128/AAC.49.2.767-769.2005. View

Wada S, Tanabe K, Yamazaki A, Niimi M, Uehara Y, Niimi K . Phosphorylation of candida glabrata ATP-binding cassette transporter Cdr1p regulates drug efflux activity and ATPase stability. J Biol Chem. 2004; 280(1):94-103. DOI: 10.1074/jbc.M408252200. View

Park S, Kelly R, Kahn J, Robles J, Hsu M, Register E . Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother. 2005; 49(8):3264-73. PMC: 1196231. DOI: 10.1128/AAC.49.8.3264-3273.2005. View

Marr K, Lyons C, Ha K, Rustad T, White T . Inducible azole resistance associated with a heterogeneous phenotype in Candida albicans. Antimicrob Agents Chemother. 2000; 45(1):52-9. PMC: 90239. DOI: 10.1128/AAC.45.1.52-59.2001. View

Uchida K, Nishiyama Y, Yokota N, Yamaguchi H . In vitro antifungal activity of a novel lipopeptide antifungal agent, FK463, against various fungal pathogens. J Antibiot (Tokyo). 2001; 53(10):1175-81. DOI: 10.7164/antibiotics.53.1175. View

MAEBASHI K, Niimi M, Kudoh M, FISCHER F, Makimura K, Niimi K . Mechanisms of fluconazole resistance in Candida albicans isolates from Japanese AIDS patients. J Antimicrob Chemother. 2001; 47(5):527-36. DOI: 10.1093/jac/47.5.527. View

Nakamura K, Niimi M, Niimi K, Holmes A, Yates J, Decottignies A . Functional expression of Candida albicans drug efflux pump Cdr1p in a Saccharomyces cerevisiae strain deficient in membrane transporters. Antimicrob Agents Chemother. 2001; 45(12):3366-74. PMC: 90839. DOI: 10.1128/AAC.45.12.3366-3374.2001. View

Smriti , Krishnamurthy S, Dixit B, Gupta C, Milewski S, Prasad R . ABC transporters Cdr1p, Cdr2p and Cdr3p of a human pathogen Candida albicans are general phospholipid translocators. Yeast. 2002; 19(4):303-18. DOI: 10.1002/yea.818. View

Bachmann S, Patterson T, Lopez-Ribot J . In vitro activity of caspofungin (MK-0991) against Candida albicans clinical isolates displaying different mechanisms of azole resistance. J Clin Microbiol. 2002; 40(6):2228-30. PMC: 130826. DOI: 10.1128/JCM.40.6.2228-2230.2002. View

10.

Denning D . Echinocandins: a new class of antifungal. J Antimicrob Chemother. 2002; 49(6):889-91. DOI: 10.1093/jac/dkf045. View

11.

Ernst E, Roling E, Petzold C, Keele D, Klepser M . In vitro activity of micafungin (FK-463) against Candida spp.: microdilution, time-kill, and postantifungal-effect studies. Antimicrob Agents Chemother. 2002; 46(12):3846-53. PMC: 132786. DOI: 10.1128/AAC.46.12.3846-3853.2002. View

12.

Wada S, Niimi M, Niimi K, Holmes A, Monk B, Cannon R . Candida glabrata ATP-binding cassette transporters Cdr1p and Pdh1p expressed in a Saccharomyces cerevisiae strain deficient in membrane transporters show phosphorylation-dependent pumping properties. J Biol Chem. 2002; 277(48):46809-21. DOI: 10.1074/jbc.M207817200. View

13.

Niimi M, Nagai Y, Niimi K, Wada S, Cannon R, Uehara Y . Identification of two proteins induced by exposure of the pathogenic fungus Candida glabrata to fluconazole. J Chromatogr B Analyt Technol Biomed Life Sci. 2002; 782(1-2):245-52. DOI: 10.1016/s1570-0232(02)00668-2. View

14.

Pfaller M, Diekema D, Messer S, Hollis R, Jones R . In vitro activities of caspofungin compared with those of fluconazole and itraconazole against 3,959 clinical isolates of Candida spp., including 157 fluconazole-resistant isolates. Antimicrob Agents Chemother. 2003; 47(3):1068-71. PMC: 149290. DOI: 10.1128/AAC.47.3.1068-1071.2003. View

15.

Schuetzer-Muehlbauer M, Willinger B, Krapf G, Enzinger S, Presterl E, Kuchler K . The Candida albicans Cdr2p ATP-binding cassette (ABC) transporter confers resistance to caspofungin. Mol Microbiol. 2003; 48(1):225-35. DOI: 10.1046/j.1365-2958.2003.03430.x. View

16.

Bartizal C, Odds F . Influences of methodological variables on susceptibility testing of caspofungin against Candida species and Aspergillus fumigatus. Antimicrob Agents Chemother. 2003; 47(7):2100-7. PMC: 161835. DOI: 10.1128/AAC.47.7.2100-2107.2003. View

17.

Arikan S, Yurdakul P, Hascelik G . Comparison of two methods and three end points in determination of in vitro activity of micafungin against Aspergillus spp. Antimicrob Agents Chemother. 2003; 47(8):2640-3. PMC: 166107. DOI: 10.1128/AAC.47.8.2640-2643.2003. View

18.

Kartsonis N, Nielsen J, Douglas C . Caspofungin: the first in a new class of antifungal agents. Drug Resist Updat. 2003; 6(4):197-218. DOI: 10.1016/s1368-7646(03)00064-5. View

19.

Magaldi S, Mata-Essayag S, Hartung de Capriles C, Perez C, Colella M, Olaizola C . Well diffusion for antifungal susceptibility testing. Int J Infect Dis. 2003; 8(1):39-45. DOI: 10.1016/j.ijid.2003.03.002. View

20.

Lee M, Williams L, Warnock D, Arthington-Skaggs B . Drug resistance genes and trailing growth in Candida albicans isolates. J Antimicrob Chemother. 2003; 53(2):217-24. DOI: 10.1093/jac/dkh040. View