ArticleEukaryotic cell2013
The calcineurin pathway inhibitor tacrolimus enhances the in vitro activity of azoles against Mucorales via apoptosis.
Article in Eukaryotic cell, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 41 citations in OpenAlex.
- Brazilian task force for the management of mucormycosis.The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious DiseasesGuideline
- Combinations of posaconazole and tacrolimus are effective against infections with azole-resistantFrontiers in cellular and infection microbiology · 2025Article
- Mucormycosis after liver transplant: Case series and literature review.Medical mycology case reports · 2024Article
- Development of a yeast cell based method for efficient screening of high yield tacrolimus production strain.3 Biotech · 2024Article
- Epidemiology, Modern Diagnostics, and the Management of Mucorales Infections.Journal of fungi (Basel, Switzerland) · 2023Review
- Augmenting Azoles with Drug Synergy to Expand the Antifungal Toolbox.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Donor-derived renal allograft mucormycosis in a combined liver and kidney transplantation: Case report and review of the literature.Transplant infectious disease : an official journal of the Transplantation Society · 2021Review
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- Article
- Calcium-Calmodulin-Calcineurin Signaling: A Globally Conserved Virulence Cascade in Eukaryotic Microbial Pathogens.Cell host & microbe · 2019Review
- Global Epidemiology of Mucormycosis.Journal of fungi (Basel, Switzerland) · 2019Review
- Article
- Scanning Quadrupole Data-Independent Acquisition, Part B: Application to the Analysis of the Calcineurin-Interacting Proteins during Treatment of Aspergillus fumigatus with Azole and Echinocandin Antifungal Drugs.Journal of proteome research · 2018Article
- Regulated Cell Death as a Therapeutic Target for Novel Antifungal Peptides and Biologics.Oxidative medicine and cellular longevity · 2018Review
- Synergistic Effects of Tacrolimus and Azoles against Exophiala dermatitidis.Antimicrobial agents and chemotherapy · 2017Article
- FKBP12-Dependent Inhibition of Calcineurin Mediates Immunosuppressive Antifungal Drug Action inmBio · 2017Article
- The antifungal pipeline: a reality check.Nature reviews. Drug discovery · 2017Review
- Regulated Forms of Cell Death in Fungi.Frontiers in microbiology · 2017Review
- Article
- In vitro interactions of antifungal agents and tacrolimus against Aspergillus biofilms.Antimicrobial agents and chemotherapy · 2015Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The calcineurin pathway regulates antifungal drug resistance and the virulence of several major human-pathogenic fungi, including the recalcitrant Mucorales. We hypothesized that the fungistatic triazoles posaconazole (PCZ) and itraconazole (ICZ) become fungicidal in the setting of the calcineurin inhibitor tacrolimus (TCR) and that such an effect is mediated through apoptosis. Fungicidal activity and apoptosis were studied using standard microbiological techniques and hyphal metabolic and vital dye reduction assays at 37°C in RPMI 1640. Apoptosis was characterized by detecting intracellular Ca(2+), phosphatidylserine (PS) externalization, DNA fragmentation, plasma membrane integrity, chromatin condensation, reactive oxygen species (ROS) generation, caspase-like activity, ATP, and cytochrome c release. MICs for PCZ and ICZ alone were significantly higher (8 to 128 μg/ml) than those of PCZ or ICZ plus TCR (0.25 to 4 μg/ml) for Rhizopus oryzae, Cunninghamella bertholletiae, and Mucor circinelloides. Both PCZ and ICZ in combination with TCR became fungicidal, and their activity was mediated through increased apoptotic cell death of R. oryzae (10 to 50%), C. bertholletiae (5 to 50%), and M. circinelloides (5 to 55%) germlings, with morphological apoptotic changes characterized by externalization of PS, nuclear condensation, and DNA fragmentation. Moreover, activation of the caspase-like activity was correlated with cell death induced by TCR plus PCZ or ICZ. These changes correlated with elevated intracellular Ca(2+) and ROS levels and disturbance of mitochondrial potential. We found that PCZ or ICZ in combination with TCR renders Mucorales sensitive to triazoles via apoptotic death. These observations could serve as a new paradigm for the development of new therapeutic strategies.
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