Introduction: With the possible spread of resistance to artemisinin combination therapies from the Greater Mekong subregion to Africa, it is vital to proactively identify anti-plasmodial compounds with alternative mechanisms of action: not only to artemisinin but all other previously and currently utilized anti-plasmodial drugs. Novel compound screening approaches with high throughput capabilities will enable front loading of compounds with various activity profiles prior to chemical class selection. Thus, placing potential alternative mechanism of action before chemical selection for hit to lead prioritization.
Method: The Pathogen box, an open source compound library consisting of 400 compounds, contains 125 compounds with anti-plasmodial activity accredited to them. Accompanying the compounds set is the screening data for both asexual blood stage, the mature stage sexual forms (stage V gametocytes) and the liver forms of Plasmodium falciparum by MMV collaborating screening platforms. Utilizing small compound handling capabilities and novel image analysis screening assays, we have extended this data set to determine the onset of compound action, first or second-generation activity, and gametocyte activity profiling from the earliest forms (Ring stage gametocytes) to those of late stage gametocytes (stage IV).
Results: Analysis of the extended data obtained has classified the 125 compounds into 9 subsets based on their onset of action, asexual blood stage and gametocyte activity profiles.
Conclusion: We believe that this data may provide a basis for selection of compounds with alternative mechanisms of action for front loading anti-malarial drug discovery efforts.