Why are iron chelators not as effective as artemisinin in killing malaria parasites?

Background It is currently established that artemisinin kills malaria parasites by disrupting iron or haem utilization. Similarly, iron chelators also eliminate these parasites by interfering with iron utilization. However, the antimalarial effect of artemisinin is significantly greater than that of iron chelators. Understanding the differences between these two mechanisms is beneficial for elucidating the antimalarial action of artemisinin and for developing strategies to enhance artemisinin-based combination therapies. Methods We employed single-cell RNA sequencing analysis to assess the sensitivity of different stages of P. falciparum 3D7 to dihydroartemisinin (DHA) and desferrioxamine (DFO) at 3, 9, and 24 hours post-treatment. Additionally, we compared the distinct antimalarial effects of artemether, DHA, and DFO on malaria parasites in vitro and in vivo. Transmission electron microscopy (TEM) was utilized to observe the effects of artemisinin on the parasites. Results Our findings indicate that P. falciparum 3D7 is more sensitive to DFO than DHA at 12, 18, 24, and 30 hours post-infection; however, 24 hours post-treatment, all stages exhibit greater sensitivity to DHA than DFO. Notably, at 3 hours post-treatment with DFO and DHA, the number of various stages changed minimally, yet iron utilization-related genes were significantly upregulated only in the DHA treatment group. Gene expression analysis revealed that the actions of DFO and DHA result in the expression of different genes, particularly those involved in ribosome synthesis and protein translation in the DHA treatment group. Although both DHA and DFO can reduce the infection rate of P. falciparum 3D7 in vitro, DFO fails to inhibit the growth of Plasmodium yoelii 17XNL in vivo. Furthermore, the combined effect of DHA and DFO is weaker than that of DHA alone. TEM analysis demonstrates that artemether disrupts haem aggregation within the digestive vacuole of malaria parasites. Conclusions While both artemisinin and iron chelators can disturb or prevent iron utilization, they kill malaria parasites through distinct mechanisms and yield different effects. Notably, the accumulation of artemisinin and its unique interaction with haem in the digestive vacuole facilitate a more efficient and specific antimalarial effect of artemisinin.