Plasmodium is thriving on iron. One of the first mistakes of Western medicine in Africa was the iron supplementation to the Somali nomads in 1968. Blood analysis of these nomads had shown that according to European standards they were suffering from anemia (MJ Murray et al., Brit Med J. Oct 1978, 1113-1116). But iron administration was associated with a significant increase of the disease it was supposed to suppress and even to reactivation of pre-existing diseases. The conclusion of the authors was that iron deficiency eventually plays a part in suppressing certain infections
PLASMODIUM ALSO NEEDS ZINC
Zinc plays a central role in many cellular processes and biochemical reactions. Prior discoveries of Plasmodium falciparum infection showed the parasite’s extraordinary ability to accumulate high levels of ‘free’ or weakly bound zinc. This metal, which appeared to be concentrated within mitochondrial space, seems to be an essential component for parasite growth and development. Zinc limitation inhibits parasite growth, suggesting a significant requirement for the metal.
This may be important as Plasmodium drives a developmentally important compartmentalization of zinc in parallel with iron redistribution and hemozoin formation. Plasma zinc concentrations are depressed during the acute phase response in children, as was observed on a cohort of 689 children from Ghana, Tanzania, Zambia (C Duggan et al, J Nutr 2005, 135, 802-7). The parasite-driven fluxes of weakly bound zinc into infected erythrocytes are essential to pathogenicity (RG Marvin et al., Chemistry & Biology 2012, 19, 731-741). The authors find that iron concentrations on the other hand do not change between uninfected and infected erythrocytes. But the Plasmodium falciparum parasite requires acquisition of 30 million zinc atoms before host cell rupture, corresponding to a 400% increase in total zinc concentration. The average zinc concentration in infected host cells containing a schizont-stage parasite was found to be 4-fold higher than in uninfected cells and localized zinc concentrations exceeded average zinc levels within the erythrocyte by over 20-fold. The same authors showed that the zinc chelators TPEN (tetrakis-pyridylmethyl-ethylene-diamine), EDTA (ethylenediaminetetraacetic acid), TETA (triethylene-tetramine), DMSA (dimercaptosuccinic acid) were highly active against the Plasmodium parasite at micromolar concentrations. Highly zinc-specific chelators are shown to inhibit the growth of the parasite while causing an arrest in development at the trophozoite stage. Dipicolinic acid (DPA) like other chelators was also found to inhibit the intracellular development of the parasite with an ED50 of 1 mM (H Ginsburg et al., Biochim Biophys Acta 1986, 886, 337-44). These data indicate that if enough chelator is available survival of the parasite is no longer possible. These chelator treatments result in a depolarization of Plasmodium mitochondria, which suggests a mechanism of chelator-induced cell death via mitochondrial disruption. But the action of these chelators is slow, up to 48 hours. Free zinc also concentrates in compartments encircling merozoites and the merozoites retain zinc after rupture from the erythrocyte host. In her thesis the same author had studied the effect of some known antimalarials and they all deplete zinc in infected erythrocytes (RG Marvin, Northwestern University, Evanston, 2009).
IC₅₀ (nM) for the growth inhibition of the 3D7 strain of Plasmodium falciparum as determined in that study were:
- Atovaquone: 0.26
- Halofantrine: 3.30
- Pyrimethamine: 12.5
- Artemisinin: 16.4
- Mefloquine: 45.2
- Chloroquine: 410
- Quinine: 1 200
- Daphnetin: 32 000
- Clindamycin: 140 000
The same thesis finds an excellent correlation between these antiplasmodial IC₅₀ values and the reduction of bioavailable zinc in parasite containing cells. It is the first time that such a correlation between zinc chelation and the efficiency of common antimalarials is described.
THE DISCOVERY OF THE PALESTINIANS
This is in line with the very surprising finding of our partners at the Al Quds University in JERUSALEM that a zinc-arginine complex strongly inhibits beta-hematin crystallization, but that zinc or arginine alone are not effective (Mutaz Akkawi, personal communication). It is the very first time that this type of inhibition is described for amino acid- zinc complexes. In fact all amino acids form soluble complexes with zinc. It is possible that these inhibit beta-hematin formation as Zn-protoporphyrin (J Martiney et al., Molecular Medicine, 1996, 2, 236-246) or zinc-desferrioxamine complexes do (M Chevion et al., Antimicrob Ag and Chemotherapy, 1995, 39, 1902-5). Indeed the Palestinians have recently developed a complex between ZnCl₂ and 2-aminopyridine dodecane which shows beta-hematin inhibition only slightly inferior to chloroquine or amodiaquine (Hijazu Abu Ali et al., J Coordination Chem. 2016 doi 10.1080/00958972).
All these studies show zinc chelators have a tremendous potential in the treatment of malaria through the control of cellular zinc homeostasis. Chelation therapy is a known medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding metals to form complex structures which are easily excreted from the body removing them from intracellular and extracellular spaces (S Flora et al., Int J Envir Res Public Health 2010, 245-2788).