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Open Access Research article

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

Serena Cervantes1, Paige E Stout23, Jacques Prudhomme1, Sebastian Engel2, Matthew Bruton1, Michael Cervantes1, David Carter4, Young Tae-Chang56, Mark E Hay3, William Aalbersberg7, Julia Kubanek23 and Karine G Le Roch1*

Author Affiliations

1 Department of Cell Biology and Neuroscience, University of California Riverside, Riverside, CA 92521, USA

2 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA

3 School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA

4 Institute for Integrative Genome Biology, University of California, Riverside, CA 92521, USA

5 Laboratory of Bioimaging Probe Development, Singapore Bioimaging Consortium, Biopolis 138667, Singapore

6 Agency for Science, Technology and Research (A*STAR), Biopolis 138667, Singapore

7 Institute of Applied Sciences, University of the South Pacific, Suva, Fiji

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BMC Infectious Diseases 2012, 12:1  doi:10.1186/1471-2334-12-1

Published: 3 January 2012

Abstract

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.

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