ANTIMALARIAL ACTION OF HYDROXAMATE-BASED IRON CHELATORS AND POTENTIATION OF DESFERRIOXAMINE ACTION BY REVERSED SIDEROPHORES

Hydroxamate-based chelators of iron are patent inhibitors of in vitro growth of Plasmodium falciparum. Two types of such chelators, the natu ral desferrioxamine and the synthetic reversed siderophore RSF(ileum2) , are prototypes of antimalarial agents whose action spectra differ in the speed of action, stage dependence, and degree of reversibility of effects. This work explores the possibility of improving the antimala rial efficacy of these agents by using them in various combinations on in vitro cultures of P. falciparum. Growth assessment was based both on total nucleic acid synthesis and on parasitemia. The results indica te that the synthetic reversed siderophore more than complements the a ntimalarial action of desferrioxamine when applied during either ring, trophozoite, or mixed stages. The combined drug effects were signific antly higher than the additive effect of the individual drugs. Qualita tively similar results were obtained for both reversible effects and i rreversible (i.e., sustained) effects. Following an 8-h window of expo sure the combined drug treatment caused parasite growth arrest and pre vented its recovery, even 3 days after the treatment. The fact that su ch a combination of iron chelators displays a wider action spectrum th an either drug alone has implications for the design of chemotherapy r egimens.