Malaria is a major global health problem, with some 212 million cases and 429,000 deaths estimated in 2015 alone. Antimalarial drugs are critical for treatment and eradication efforts. However, resistance to clinically approved drugs is rapidly spreading. At the same time, the pipeline of new antimalarial drugs is limited. Phenotypic screens have been valuable in discovering promising lead compounds, but identifying the target of these compounds is a separate, time-consuming process. Towards overcoming this critical bottleneck in lead compound discovery and optimization, we have combined genetic strategies for specifically titrating the expression of essential parasite target proteins with chemical screens to identify functional interactions between compounds and parasite targets. In this way, we simultaneously obtain evidence of the antimalarial activity of a compound and its likely mode of action within the rapid timeframe of a phenotypic screen. We show that this approach efficiently detects interactions between specific compounds and their targets, and importantly, also allows specific targets to be ruled out in mode of action studies on antimalarial compounds. We envision this target-based phenotypic screening approach will be scalable, and are currently integrating it with high throughput screening platforms towards the goal of improving the efficiency with which promising lead antimalarial compounds can be advanced towards clinical translation.

Target-specific phenotypic screening for rapid and scalable antimalarial drug discovery

254th National Meeting (2017)

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