Antimicrob Agents Chemother. 2012 Aug 20. [Epub ahead of print]
A focused small molecule screen identifies 14 compounds with distinct effects on Toxoplasma gondii
Kamau ET, Srinivasan AR, Brown MJ, Fair MG, Caraher EC, Boyle JP.
University of Pittsburgh, Department of Biological Sciences, Pittsburgh, PA. 15260.
Toxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in immunocompromised humans and the developing fetus. Given the proven role of Toxoplasma secreted kinases in the interaction of Toxoplasma with its host cell, identification of novel kinase inhibitors could precipitate the development of new anti-Toxoplasma drugs and define new pathways important for parasite survival. We selected a small (527), but diverse, set of putative kinase inhibitors and screened them for effects on the growth of Toxoplasma in vitro. We identified and validated 14 noncytotoxic compounds, all of which have EC50s in the nanomolar to micromolar range. We further characterized 8 of these compounds, 4 inhibitors and 4 enhancers, by determining their effects on parasite motility, invasion, and the likely cellular target (parasite or host cell). Only two compounds had an effect on parasite motility and invasion. All the inhibitors appear to target the parasite and interestingly, two of the enhancers appear to rather target the host cell, suggesting modulation of host cell pathways beneficial for parasite growth. For the four inhibitors, we also tested their efficacy in a mouse model where one compound proved potent. Overall these 14 compounds represent a new and diverse set of small molecules that are likely targeting distinct parasite and host cell pathways. Future work will aim to characterize their molecular targets in both the host and parasite.
PMID: 22908155 [PubMed - as supplied by publisher]