In vitro screening of the open source MMV malaria box reveals novel compounds with profound activities against Theileria annulata schizonts

14 Mar 2016

Hostettler I, Müller J, Hemphill A.

Antimicrobial Agents and Chemotherapy

DOI: 10.1128

Abstract

Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leukocytes and thereby cause fatal diseases. The hydroxynaphthoquinone buparvaquone is currently the only option for the treatment of theileriosis, and resistance formation has been reported. It is therefore tempting to investigate the repurposing of compounds effective against related apicomplexan parasites such as Plasmodium. Here, we present the results of a screen of 400 compounds included in the open access Medicines for Malaria Venture (MMV) malaria box on TaC12 cells, a macrophage-derived cell line immortalized by T. annulata schizonts. Using a combination of the classical Alamar blue vitality assay and a recently developed quantitative reverse transcriptase real time PCR method based on the Theileria gene TaSP, we have identified 5 compounds, characterized their effects on the ultrastructure of TaC12 cells, and investigated whether they easily induce resistance formation. Two compounds, the quinolinols MMV666022 and MMV666054, have IC50 values of 0.5 and 0.2 μM on TaC12 cells and 5.3 and 5.2 μM on BoMac cells respectively. Thus, with therapeutic indexes of 11 and 18, they represent promising leads for further development of anti-theilerial chemotherapeutics.