Synergistic Antifungal Activities of Bafilomycin A 1 , Fluconazole, and the Pneumocandin MK-0991/Caspofungin Acetate (L-743,873) with Calcineurin Inhibitors FK506 and L-685,818 against Cryptococcus neoformans

Del Poeta, Maurizio; Cruz, M. Cristina; Cardenas, Maria E.; Perfect, John R.; Heitman, Joseph

doi:10.1128/aac.44.3.739-746.2000

Cited by 169Fungal Infections and StudiesAntifungal resistance and susceptibilityFungal Plant Pathogen Control

Synergistic Antifungal Activities of Bafilomycin A 1 , Fluconazole, and the Pneumocandin MK-0991/Caspofungin Acetate (L-743,873) with Calcineurin Inhibitors FK506 and L-685,818 against Cryptococcus neoformans

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Del Poeta, Maurizio, Cruz, M. Cristina, Cardenas, Maria E., Perfect, John R., Heitman, Joseph·2000·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.44.3.739-746.2000PMC PMC89756

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Abstract

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 degrees 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 A(1) 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.

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Calcineurin inhibitors synergize with fluconazole against C. neoformans.
“Calcineurin inhibitors also synergize with fluconazole against C. neoformans (Del Poeta et al. 2000)”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Del Poeta et al. 2000

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Rivera, A., Lim, W. Y., Park, E., Dome, P. A., Hoy, M. J., Spasojević, I., Sun, S., Averette, A. F., Piña‐Oviedo, S., Juvvadi, P. R., et al. (2023) · mBio · doi:10.1128/mbio.01810-23 · Cited by 5 · see citing works
Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro
Franzot, S. P., & Casadevall, A. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.2.331 · Cited by 124 · see citing works
Calcineurin regulatory subunit is essential for virulence and mediates interactions with FKBP12–FK506 in Cryptococcus neoformans
Fox, D. S., Cruz, M. C., Sia, R. A. L., Ke, H., Cox, G. M., Cardenas, M. E., & Heitman, J. (2001) · Molecular Microbiology · doi:10.1046/j.1365-2958.2001.02295.x · Cited by 175 · see citing works
Synergistic Effect of Calcineurin Inhibitors and Fluconazole against Candida albicans Biofilms
Uppuluri, P., Nett, J., Heitman, J., & Andes, D. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01397-07 · Cited by 228 · see citing works

Authors: Del Poeta, M., Cruz, M. C., Cardenas, M. E., Perfect, J. R., & Heitman, J.
Affiliations: Departments of Medicine,1
Genetics,4
Howard Hughes Medical Institute (US)
ORCID: Cruz, M. Cristina
Perfect, John R.
Heitman, Joseph
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2000-03
Volume: 44
Issue: 3
Pages: 739-746
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.44.3.739-746.2000
PMC: PMC89756
OpenAlex: W2130655869
Cited by: 169
References: 55
Citations by year: 2026: 3 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 7 · 2018: 2 · 2017: 13 · 2016: 6 · 2015: 4 · 2014: 11 · 2013: 7 · 2012: 6
FWCI: 7.48
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ai041937-03)
National Institute of Allergy and Infectious Diseases (AI41937-01S1, P01AI044975, AI-44975, AI41937)
Topics: Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords: Cryptococcus neoformans, calcineurin, FK506, bafilomycin A1, fluconazole, caspofungin acetate, drug synergy, combination antifungal therapy, FKBP12, H+-ATPase inhibition, beta-1,3-glucan synthase, multidrug resistance pumps, opportunistic fungal infection
MeSH terms: Caspofungin, Anti-Bacterial Agents, Antifungal Agents, Cryptococcus neoformans, Drug Combinations, Drug Synergism, Humans, Microbial Sensitivity Tests, Peptides, Peptides, Cyclic, Fluconazole, Tacrolimus, Macrolides, Calcineurin, Immunophilins, Tacrolimus Binding Proteins, Echinocandins, Lipopeptides, Calcineurin Inhibitors

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Synergistic Antifungal Activities of Bafilomycin A 1 , Fluconazole, and the Pneumocandin MK-0991/Caspofungin Acetate (L-743,873) with Calcineurin Inhibitors FK506 and L-685,818 against Cryptococcus neoformans

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