Revitalizing our antifungal arsenal with natural products isolated from Arctic bacteria

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

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