PLASMODIUM-FALCIPARUM - CYANIDE-RESISTANT OXYGEN-CONSUMPTION

It has been hypothesized that Plasmodium parasites utilize a branched chain respiratory pathway, consisting of a classical cyanide-sensitive branch and an alternative cyanide-resistant branch. To further explor e this hypothesis, the effect of cyanide on Plasmodium falciparum was determined using a polarographic assay. The rate of oxygen consumption by saponin-freed parasites was approximately 5% that of control human white blood cells or of Toxoplasma gondii, consistent with an anaboli c role for P. falciparum respiration. However, while all of the oxygen consumption of the control white blood cells and of T. gondii could b e inhibited by cyanide, 25% of the oxygen consumption of the P. falcip arum parasites was found to be insensitive to high concentrations of c yanide. The cyanide-resistant portion of the parasite oxygen consumpti on was completely inhibited by two inhibitors of alternative oxidase a ctivities in other systems, propyl gallate and salicyclhydroxamic acid . These studies provide the first direct evidence for a branched chain respiratory pathway in P. falciparum. Furthermore, salicyclhydroxamic acid, propyl gallate, and related inhibitors of alternative oxidase a ctivities were shown to inhibit the growth of P. falciparum in vitro. These results support the need for further investigation of alternativ e oxidase activity as an antimalarial chemotherapeutic target. (C) 199 7 Academic Press.