Author:
Evelyne Côté (CA)
Abstract:
Background: In the search for new antifungal agents, one approach is to mine the biodiversity of poorly characterized microbial ecosystems such as the Arctic. Our team screened the secretomes of a panel of newly discovered polar bacteria from Axel Heiberg Island, Nunavut, Canada. This screen identified staurosporine (STS), produced by an Arctic Streptomyces species, as exhibiting potent antifungal activity in vitro. The objective of this project is to investigate the potential of STS in the treatment of fungal disease.
Methods: The therapeutic index of STS was evaluated using two approaches. First, its antifungal activity was defined using our in vitro microbroth dilution assay against a range of fungal pathogens. This panel included drug-resistant clinical isolates. Secondly, STS cytotoxicity was investigated using in vitro assays with human cell lines. Testing of the potentiation of existing antifungals was performed using standard microbroth dilution assays. The quantification of chitin in the Aspergillus cell wall was performed using gas chromatography.
Results: At the molar level, STS exhibited similar or greater activity against all pathogens tested as compared to amphotericin B. However, significant cytotoxicity was observed at the concentrations of STS required for antifungal activity, suggesting its use as a systemic drug is limited. However, STS was found to potentiate the activity of the echinocandin antifungals caspofungin and micafungin against Aspergillus fumigatus at levels lower than the cytotoxicity threshold. This drug combination was also effective against several other fungal species, including Candida albicans and Candida auris. Given that STS has been reported to broadly inhibit protein kinases, it was hypothesized that STS might potentiate caspofungin activity by inhibiting the echinocandin-induced compensatory upregulation of chitin synthesis mediated by the kinase-dependent cell wall integrity pathway. However, the combination treatment of caspofungin and STS was found to increase the chitin content in the Aspergillus cell wall to a higher level than was observed with echinocandin monotherapy. This observation suggests that the antifungal activity of STS is mediated by a mechanism other than inhibition of the cell wall integrity pathway.
Conclusions: These studies have the potential to advance the development of an urgently needed solution for drug-resistant fungal infections. Further studies are ongoing, including phosphoproteomics to probe the mechanism of staurosporine against Aspergillus, and animal studies to investigate the efficacy of the echinocandin and staurosporine drug combination in vivo.
Abstract Number: 88
Conference Year: 2024
Conference abstracts, posters & presentations
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Title
Author
Year
Number
Poster
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v
Jannik Stemler* 1;2;3, Caroline Bruns 1;2;3, Sibylle Mellinghoff 1;2;3, Philipp Köhler 1;2, Oliver A. Cornely 1;2;3;4
1720
n/a
-
v
Camille Mane* 1, Véronique Duhalde 2, Isabelle Labadens 2, Olivier Cointault 2, Didier Concordet 1, Peggy Gandia 1;2
1607
n/a
-
v
Ester Fusté 1, Guadalupe Jimenez Galisteo 2, M. Jesus Sanchez 3, Mercedes Aguilar 4, Teresa Vinuesa* 2
1317
n/a
-
v
Antonio Arrieta* 1, Michael Neely 2, James Day 3, Susan Rheingold 4, Paul Sue 5, William Muller 6, Lara Danziger-Isakov 7, Julie Chu 8,
Inci Yildirim 9, Grace Mccomsey 10, Haydar Frangoul 11, Tempe Chen 12, Victoria Statler 13, William Steinbach 14, Dwight Yin 3, Kamal Hamed 15, Christopher Lademacher 16, Amit Desai 16, Jamie Akin 16, Desiree Leiva Phillips 16, Laura Kovanda 16, Thomas J. Walsh 171191
n/a
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v
Birgit Spiess* 1, Tobias Boch 1, Maximilian Mossner 2, Daniel Nowak 1, Julian Skladny 1, Cornelia Lass-Flörl 3, Oliver Bader 4, Thomas Miethke 5, Jörg Steinmann 6, Peter-Michael Rath 7, Anne Dietz 5, Natalia Merker 1, Verena Nowak 1, Wolf-Karsten Hofmann 1, Dieter Buchheidt 1
1142
n/a
-
v
Fiona Senchyna* 1, Catherine Hogan 1;2, Dora Ho 1, Aruna Subramanian 1, Indre Budvytiene 2, Saurabh Gombar 1, Helio Costa 1;2, Martynas Budvytis 3 , Niaz Banaei 1;2
1036
n/a
-
v
Malene Risum* 1, Rasmus Krøger Hare 1, Jan Berg Gertsen 2, Lise Kristensen 2, Flemming Rosenvinge 3, Sofia Sulim 4, Ea Marmolin 5, Bent Løwe Røder 6, Jette Bangsborg 7, Esad Dzajic 8, Michael Pedersen 9, Karen Marie Thyssen Astvad 9, Steen Lomborg Andersen 10, Maiken C. Arendrup 1;11;12
980
n/a
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v
Karina Monosova* 1, Maria Simonenko 1, Yulia Sazonova 1, Ksenia Zagorodnikova 1, Larisa Vasiljeva 1, Rubinchik Vadim 1, Maria Bortsova 1, Petr Fedotov 1
975
n/a
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v
Judith Diaz-Garcia*1;2; Pilar Escribano 1;2; Julia Serrano 1;2; Belen Rodriguez-Sanchez 1;2; Estreya Zvezdanova 1;2; M Teresa Martin Gomez 3; Elisa Ibañez Martinez 4; Maria Rodriguez Mayo 5; Teresa Pelaez Garcia 6; Elia García G. De La Pedrosa 7; Rocío Tejero-García 8; Jose Maria Marimon 9; Elena Reigadas Ramirez 1;2; Antonio Rezusta 10; Cristina Labayru Echeverría 11; Ana Perez De Ayala Balzola 12; Josefina Ayats 13; Fernando Cobo 14; María Del Carmen Pazos Pacheco 15; Patricia Muñoz 1;2;16;17; Jesus Guinea Ortega 1;2;17
896
n/a
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v
Jing Zhang* 1, Yingyuan Zhang 1, Depei Wu 2, Guoying Cao 1, Kamal Hamed 3, Amit Desai 4, Jalal A. Aram 5, Xuan Guo 6, Rana Fayyad 5, Oliver A. Cornely 7;8;9
624
n/a