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Antimicrobial Agents and Chemotherapy, March 2003, p. 956-964, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.956-964.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ergosterol Biosynthesis Inhibitors Become Fungicidal when Combined with Calcineurin Inhibitors against Candida albicans, Candida glabrata, and Candida krusei

Chiatogu Onyewu,1 Jill R. Blankenship,2 Maurizio Del Poeta,3,4 and Joseph Heitman1,2,5,6*

Departments of Molecular Genetics and Microbiology,2 Medicine,5 Pharmacology and Cancer Biology,1 Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710,6 Departments of Biochemistry and Molecular Biology,3 Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 294254

Received 9 September 2002/ Returned for modification 14 November 2002/ Accepted 16 December 2002

Azoles target the ergosterol biosynthetic enzyme lanosterol 14{alpha}-demethylase and are a widely applied class of antifungal agents because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Unfortunately, azoles are generally fungistatic and resistance to fluconazole is emerging in several fungal pathogens. We recently established that the protein phosphatase calcineurin allows survival of Candida albicans during the membrane stress exerted by azoles. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) are dramatically synergistic with azoles, resulting in potent fungicidal activity, and mutant strains lacking calcineurin are markedly hypersensitive to azoles. Here we establish that drugs targeting other enzymes in the ergosterol biosynthetic pathway (terbinafine and fenpropimorph) also exhibit dramatic synergistic antifungal activity against wild-type C. albicans when used in conjunction with CsA and FK506. Similarly, C. albicans mutant strains lacking calcineurin B are markedly hypersensitive to terbinafine and fenpropimorph. The FK506 binding protein FKBP12 is required for FK506 synergism with ergosterol biosynthesis inhibitors, and a calcineurin mutation that confers FK506 resistance abolishes drug synergism. Additionally, we provide evidence of drug synergy between the nonimmunosuppressive FK506 analog L-685,818 and fenpropimorph or terbinafine against wild-type C. albicans. These drug combinations also exert synergistic effects against two other Candida species, C. glabrata and C. krusei, which are known for intrinsic or rapidly acquired resistance to azoles. These studies demonstrate that the activity of non-azole antifungal agents that target ergosterol biosynthesis can be enhanced by inhibition of the calcineurin signaling pathway, extending their spectrum of action and providing an alternative approach by which to overcome antifungal drug resistance.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, 322 Carl Building, Box 3546, Research Dr., Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu.

Antimicrobial Agents and Chemotherapy, March 2003, p. 956-964, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.956-964.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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