Authors
D T Waterhouse1; R Sharma1; D A Cook1; M T Taylor1; S A Ward1; 1 Liverpool School of Tropical Medicine Discussion
Parasitic nematodes are currently, estimated to infect one quarter of the world’s population, which has a negative impact on their quality of health and productivity. The majority of those infected reside in low to middle income countries and access to effective treatments is a challenge. The AWOL consortium was, established to discover and develop new drug treatments for these diseases based on an anti-Wolbachia mechanism of action. However, the underlying rules that govern drug partitioning and accumulation in these nematodes is unknown. The objective of the current study was to develop an in-vitro screen, using highly sensitive analytical assays, to delineate key physicochemical properties that favour drug bioaccumulation into microfilariae of Brugia malayi. Understanding these key properties is central to the preselection of molecules capable of reaching the Wolbachia in the nematode thereby increasing the hit rate of small-molecule library screens. We screened 48 commercially available human and veterinary medicines, including known anthelmintics, with a wide variety of well-characterised physicochemical properties. From our dataset, we developed a structure-based accumulation model that identifies compound characteristics that increase the probability of accumulation in and biologically activity against B. malayi. 
