Authors

R H Clare¹; N Berry²; D Hong²; K L Johnston¹; L Ford¹; D A Cook¹; J Archer¹; A Steven¹; G Nixon²; P M O'Neill²; M J Taylor¹; S A Ward¹;  ¹ Liverpool School of Tropical Medicine, UK;  ² University of Liverpool, UK

Discussion

A screening campaign through a partnership between the anti-Wolbachia consortium (A∙WOL) and AstraZeneca has identified 5 novel areas of diverse chemical space with enhanced activity against Wolbachia, an essential bacterial endosymbiont of filarial parasites. This was accomplished through the first industrial scale screening of 1.3 million of AstraZeneca’s compounds against Wolbachia, using a fully automated intracellular whole cell assay. Following a primary screen at 10µM, ~20,000 hits were triaged through chemoinformatic analysis to select 58 clusters in distinct areas of chemical space. Representatives from all 58 clusters were tested in vitro using microfilariae (Mf), resulting in 10 clusters demonstrating potent Wolbachia reduction after 6 days exposure. When tested in a Mf time kill assay, five of these clusters showed a superior rate of kill compared to all other A∙WOL drugs with activity demonstrable at less than 1 day exposure. These chemotypes, are extremely promising new leads for safe macrofilaricides against lymphatic filariasis and onchocerciasis.