Heme-dependent radical generation: Possible involvement in antimalarial action of non-peroxide microbial metabolites, nanaomycin A and radicicol

Abstract

Antimalarial screening was performed for microbial metabolites that simulate artemisinin in their mode of action, a potent antimalarial component of an herbal remedy with a characteristic peroxide structure. Nanaomycin A was identified in this screen as an antimalarial compound together with radicicol and several other compounds already reported. Nanaomycin A inhibited in vitro growth of the human malaria parasite Plasmodium falciparum with an IC80 value of 33.1 nM. It was as potent as radicicol and about 1/10 as potent as artemisinin. Studies on the mode of action suggested that the antimalarial action of the two non-peroxides, nanaomycin A and radicicol, involved heme-dependent radical generation, as is for the peroxide artemisinin. Namely, the inhibition of in vitro growth of malaria parasite by nanaomycin A or radicicol was reversed by tocopherol, a radical scavenger added to the assay mixture. Secondly, in a reaction system established for radical detection, in which a test radical donor and β-alanylhistidine as a radical recipient were incubated with and without hemin, the two compounds caused heme-dependent decreases of β-alanylhistidine, as did artemisinin. Among the 14 microbial metabolites identified during this screening, a correlation was observed between antimalarial activity and heme-dependent radical generating activity.