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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
Open accessAbstract
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 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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Metadata
- Authors
- Del Poeta, M., Cruz, M. C., Cardenas, M. E., Perfect, J. R., & Heitman, J.
- Affiliations
- <!--label omitted: 1-->Departments of Medicine,1
- <!--label omitted: 4-->Genetics,4
- Howard Hughes Medical Institute (US)
- 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
- 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
- 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 › Infectious Diseases › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Plant Science › 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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