Proteasome inhibitor, epoxomicin, has potent P. falciparum gametocytocidal activity. - Related Articles
Proteasome inhibitor, epoxomicin, has potent P. falciparum gametocytocidal activity.
Antimicrob Agents Chemother. 2009 Aug 3;
Authors: Czesny B, Goshu S, Cook JL, Williamson KC
Malaria continues to be a major global health problem, yet only a limited arsenal of effective drugs are available. None of the anti-malaria compounds commonly used clinically kill mature gametocytes, which are the form of the parasite responsible for malaria transmission. The parasite that causes the most virulent human malaria, Plasmodium falciparum, has a 48 h asexual cycle, while complete sexual differentiation takes 10-12 days. Once mature, stage V gametocytes circulate in the peripheral blood and can be transmitted for over a week. Consequently, if chemotherapy does not eliminate gametocytes, an individual continues to be infectious for several weeks after clearance of asexual parasites. The work reported here demonstrates that nanomolar concentrations of proteasome inhibitor, epoxomicin, effectively kills all stages of intraerythrocytic parasites, but does not affect the viability of human or mouse cell lines. Twenty four hours after treatment with 100 nM epoxomicin, the total parasitemia decreased by 78%, asexuals decreased by 86% and gametocytes by 77%. Seventy two hours after treatment, no viable parasites remained in the 100 nM or 10 nM treatment groups. Epoxomicin also blocked oocyst production in the mosquito midgut. In contrast, cysteine protease inhibitors epoxysuccinyl-L-leucylamido-3-methyl-butane ethyl ester (E64d) and N-acetyl-L-leucyl-L-leucyl-L-methioninal (ALLM), blocked hemoglobin digestion in early gametocytes, but had no effect on later stages. Moreover, once the cysteine protease inhibitor is removed sexual differentiation resumed. These finding provide strong support for the further development of proteasome inhibitors as anti-malaria agents that are effective against asexual, sexual, and mosquito midgut stages of P. falciparum.
PMID: 19651911 [PubMed - as supplied by publisher] [PubMed-Malaria]