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Antimicrobial Agents and Chemotherapy, March 2000, p. 739-746, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Synergistic Antifungal Activities of Bafilomycin A1, Fluconazole, and the Pneumocandin MK-0991/Caspofungin Acetate (L-743,873) with Calcineurin Inhibitors FK506 and L-685,818 against Cryptococcus neoformans

Maurizio Del Poeta,1,2,3 M. Cristina Cruz,4 Maria E. Cardenas,4 John R. Perfect,1,5 and Joseph Heitman1,4,5,6,7,*

Departments of Medicine,1 Genetics,4 Pharmacology and Cancer Biology,6 and Microbiology,5 Howard Hughes Medical Institute,7 Duke University Medical Center, Durham, North Carolina 27710; College of Medicine, Medical University of South Carolina, Charleston, South Carolina 294252; and Institute of Infectious Diseases and Public Health, University of Ancona, Ospedale Umberto I, 60121 Ancona, Italy3

Received 7 September 1999/Returned for modification 16 November 1999/Accepted 20 December 1999

Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening infections of the central nervous system. Existing therapies include amphotericin B, fluconazole, and flucytosine, which are limited by toxic side effects and the emergence of drug resistance. We recently demonstrated that the protein phosphatase calcineurin is required for growth at 37°C and virulence of C. neoformans. Because calcineurin is the target of potent inhibitors in widespread clinical use, cyclosporine and FK506 (tacrolimus), it is an attractive drug target for novel antifungal agents. Here we have explored the synergistic potential of combining the calcineurin inhibitor FK506 or its nonimmunosuppressive analog, L-685,818, with other antifungal agents and examined the molecular basis of FK506 action by using genetically engineered fungal strains that lack the FK506 target proteins FKBP12 and calcineurin. We demonstrate that FK506 exhibits marked synergistic activity with the H+ATPase inhibitor bafilomycin A1 via a novel action distinct from calcineurin loss of function. FK506 also exhibits synergistic activity with the pneumocandin MK-0991/caspofungin acetate (formerly L-743,873), which targets the essential beta -1,3 glucan synthase, and in this case, FK506 action is mediated via FKBP12-dependent inhibition of calcineurin. Finally, we demonstrate that FK506 and fluconazole have synergistic activity that is independent of both FKBP12 and calcineurin and may involve the known ability of FK506 to inhibit multidrug resistance pumps, which are known to export azoles from fungal cells. In summary, our studies illustrate the potential for synergistic activity of a variety of different drug combinations and the power of molecular genetics to define the mechanisms of drug action, as well as identify a novel action of FK506 that could have profound implications for therapeutic or toxic effects in other organisms, including humans.

* Corresponding author. Mailing address: 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 2000, p. 739-746, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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