High content live cell imaging for the discovery of new antimalarial marine natural products

BMC Infectious Diseases

Karine G Le Roch¹  Julia Kubanek³  William Aalbersberg⁵  Mark E Hay³  Young Tae-Chang²  David Carter⁴  Michael Cervantes¹  Matthew Bruton¹  Sebastian Engel⁶  Jacques Prudhomme¹  Paige E Stout⁶  Serena Cervantes¹ 

[1] Department of Cell Biology and Neuroscience, University of California Riverside, Riverside, CA 92521, USA;Agency for Science, Technology and Research (A*STAR), Biopolis 138667, Singapore;School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA;Institute for Integrative Genome Biology, University of California, Riverside, CA 92521, USA;Institute of Applied Sciences, University of the South Pacific, Suva, Fiji;School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA

关键词: High-throughput screening;    Antimalarial;    Natural products;    Drug screening;    Plasmodium falciparum;   

Others  :  1175489
DOI  :  10.1186/1471-2334-12-1

 received in 2011-06-22, accepted in 2012-01-03,  发布年份 2012

【 摘 要 】

Background

The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum.

Methods

A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope.

Results

Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts.

Conclusion

Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.

【 授权许可】

   
2011 Cervantes et al; licensee BioMed Central Ltd.

【 图 表 】

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