Combination of caspofungin with inhibitors of the calcineurin pathway attenuates growth in vitro in Aspergillus species

Kontoyiannis, Dimitrios P.; Lewis, Russell E.; Osherov, Nir; Albert, Nathaniel D.; May, Gregory S.

doi:10.1093/jac/dkg090

Cited by 111 publications

(78 citation statements)

References 12 publications

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“…In A. fumigatus, different calcineurin inhibitors enhance the activity of caspofungin and lead to attenuated growth in vitro (282,560). The deletion of cnaA, which encodes the catalytic subunit of calcineurin, similarly enhances the efficacy of caspofungin (558).…”

Section: Stress Responsementioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

499

547

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SUMMARY Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans , several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus , which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans , C. neoformans , and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

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Section: Stress Responsementioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

499

547

View full text Add to dashboard Cite

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“…Calcium signalling through the Ca 2+ -binding protein calmodulin and the Ca 2+ -calmodulin-dependent phosphatase calcineurin has been implicated in a multitude of processes, including stress response, mating, budding, and actin-based processes (Cyert, 2001) as well as in determining tolerance to antifungal drugs (Cruz et al, 2002;Del Poeta et al, 2000;Kontoyiannis et al, 2003;Sanglard et al, 2003;Steinbach et al, 2007;Walker et al, 2008). Cellular calcium levels in S. cerevisiae are regulated by multiple channels and transporters, including the voltage-gated high-affinity calcium channel Cch1 which functions together with the stretch-activated cation channel Mid1 (Locke et al, 2000).…”

Section: The Calcium/calcineurin Signalling Pathwaymentioning

confidence: 99%

Comparative genomics of MAP kinase and calcium–calcineurin signalling components in plant and human pathogenic fungi

Rispail

Soanes

Ant

et al. 2009

Fungal Genetics and Biology

285

281

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a b s t r a c tMitogen-activated protein kinase (MAPK) cascades and the calcium-calcineurin pathway control fundamental aspects of fungal growth, development and reproduction. Core elements of these signalling pathways are required for virulence in a wide array of fungal pathogens of plants and mammals. In this review, we have used the available genome databases to explore the structural conservation of three MAPK cascades and the calcium-calcineurin pathway in ten different fungal species, including model organisms, plant pathogens and human pathogens. While most known pathway components from the model yeast Saccharomyces cerevisiae appear to be widely conserved among taxonomically and biologically diverse fungi, some of them were found to be restricted to the Saccharomycotina. The presence of multiple paralogues in certain species such as the zygomycete Rhizopus oryzae and the incorporation of new functional domains that are lacking in S. cerevisiae signalling proteins, most likely reflect functional diversification or adaptation as filamentous fungi have evolved to occupy distinct ecological niches.

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“…87,88 In other studies, CsA and tacrolimus had intrinsic activity against A. fumigatus (CsA: MICs, 3-10 μg/ml; geometric mean MIC, 6.25 μg/ml; tacrolimus: MICs, 0.2-0.4 μg/ml; geometric mean MIC, 1.56 μg/ml). 66,89 Calcineurin and TOR inhibitors also have converted azoles (e.g., itraconazole) and the echinocandin caspofungin into fungicidal compounds against A. fumigatus, A. flavus and Aspergillus terreus. [87][88][89] Inhibition of the calcineurin and TOR pathways may decrease the threshold of deleterious effects of echinocandins.…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

“…66,89 Calcineurin and TOR inhibitors also have converted azoles (e.g., itraconazole) and the echinocandin caspofungin into fungicidal compounds against A. fumigatus, A. flavus and Aspergillus terreus. [87][88][89] Inhibition of the calcineurin and TOR pathways may decrease the threshold of deleterious effects of echinocandins. Alternatively, combinations of caspofungin and calcineurin inhibitors may inhibit expression of the A. fumigatus FKS1 homolog.…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

“…Alternatively, combinations of caspofungin and calcineurin inhibitors may inhibit expression of the A. fumigatus FKS1 homolog. 89 As for Candida spp., longterm CsA and tacrolimus exposure in vivo did not make these species resistant to these agents. 88 Animal data have indirectly confirmed the CsA-and tacrolimus-induced anti-Aspergillus effects described above in vivo.…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

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