A Non-Echinocandin Compound Isolated from a Marine Sponge Mediates its Antifungal Activity by Targeting the Fungal Cell Wall

Ref ID: 18683

Author:

S. Tripathi, PhD – Postdoctoral Associate, T. Xu, PhD – Postdoctoral Associate, Q. Feng, MS – Senior R & D Biologist, M. Jacob, PhD – Research Scientist, W. Xu, PhD – Postdoctoral Associate, X. Li, PhD – Senior Scientist, A. Clark, PhD – Professor, A

Author address:

Univ. of Mississippi, University, MS.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Due to the increase in drug resistance and the rise in opportunistic fungal infections, new antifungal drugs that target new pathways are greatly needed. We have isolated agelasine D (AGEL), a purine-diterpene alkaloid from a marine sponge, which exhibits antifungal activity against several fungal pathogens including Cryptococcus neoformans, Candida albicans and Aspergillus fumigatus. In this study, we have investigated its mechanism of action in the model yeast, Saccharomyces cerevisiae. Methods: Transcriptional profiling was conducted to monitor gene expression changes in yeast cells exposed to AGEL at the IC50 concentration for one doubling time. Statistically significant differentially expressed genes were identified using BRB Array Tools software. Yeast strains lacking candidate genes from pathways identified in the profiling study were analyzed by drop-test assays. Finally, checkerboard assays were performed to further confirm the profiling results. All experiments were performed in either duplicates or triplicates. Results: Transcriptional profiling with AGEL indicated the upregulation of genes involved in cell wall organization, and the downregulation of genes involved in mating response, a profile very similar to that of the cell wall-inhibiting echinocandin antifungal drug caspofungin (CPF). Yeast strains with deletions in genes involved in cell wall maintenance were hypersusceptible to AGEL. In a checkerboard assay, the antifungal activities of AGEL and CPF were synergistic with each other. In the CPF-insensitive fungal pathogen, C. neoformans, the combination of AGEL and CPF produced a fungicidal effect at non-inhibitory concentrations. Conclusions: Taken together, our studies indicate that AGEL, a marine compound with no similarity to the echinocandin class of compounds, mediates its antifungal activity by targeting the fungal cell wall. Our work also reveals that AGEL could have potential use in combination therapy with cell wall inhibitors such as CPF, thus providing a means to eliminate fungal pathogens such as Cryptococcus sp., which are inherently CPF-insensitive.

Abstract Number: M-1061

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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