Authors

Discussion

Leishmania donovani is the causative agent of visceral leishmaniasis, with an estimated 300,000 cases and 20,000 deaths annually. There is an urgent need for new treatment therapies as the current options involve high cost, lengthy regimes, toxicity and emerging drug resistance The University of Dundee Drug Discovery Unit and GSK have set up a collaboration focused on developing new drugs for visceral leishmaniasis.Free living parasites (promastigotes or axenic amastigotes) have been used by many groups for compound screening. Poor translation between these assays and the more physiologically relevant intracellular assay has often been observed. In our screening cascade we either perform primary screening using a medium-throughput intracellular assay, or for higher throughput we use an axenic amastigote assay that has been optimised to detect only cytocidal compounds.

Here we describe the results of two hit-finding campaigns, one conducted with the intracellular amastigote assay (GHCDL (68,320 compounds)), and a second that focused on re-assessing hits from a large high-throughput screen (2 million compounds) carried out with axenic amastigotes. For this reassessment we put in place a screening cascade comprising of compound prioritisation, cidality profiling and