In Vitro Activity of Anti-malarial Ozonides Against an Artemisinin-resistant Isolate

Background: Recently published data suggest that artemisinin derivatives and synthetic peroxides, such as the ozonides OZ277 and OZ439, have a similar mode of action. Here the cross-resistance of OZ277 and OZ439 and four additional next-generation ozonides was probed against the artemisinin-resistant clinical isolate Plasmodium falciparum Cam3.I, which carries the K13-propeller mutation R539T (Cam3.I).

Methods: The previously described in vitro ring-stage survival assay (RSA) was employed and a simplified variation of the original protocol was developed.

Results: At the pharmacologically relevant concentration of 700 nM, all six ozonides were highly effective against the dihydroartemisinin-resistant P. falciparum Cam3.I parasites, showing a per cent survival ranging from <0.01 to 1.83%. A simplified version of the original RSA method was developed and gave similar results, thus providing a practical drug discovery tool for further optimization of next-generation anti-malarial peroxides.

Conclusion: The absence of in vitro cross-resistance against the artemisinin-resistant clinical isolate Cam3.I suggests that ozonides could be effective against artemisinin-resistant P. falciparum. How this will translate to the human situation in clinical settings remains to be investigated.