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Antimicrobial Agents and Chemotherapy, October 2009, p. 4080-4085, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00088-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Proteasome Inhibitor Epoxomicin Has Potent Plasmodium falciparum Gametocytocidal Activity{triangledown}

Beata Czesny,1 Samrawit Goshu,1 James L. Cook,2 and Kim C. Williamson1*

Department of Biology, Loyola University Chicago, Chicago, Illinois,1 Section of Infectious Diseases, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois2

Received 21 January 2009/ Returned for modification 2 March 2009/ Accepted 17 July 2009

Malaria continues to be a major global health problem, but only a limited arsenal of effective drugs is available. None of the antimalarial compounds commonly used clinically kill mature gametocytes, which is the form of the parasite that is 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 to 12 days. Once mature, stage V gametocytes circulate in the peripheral blood and can be transmitted for more than a week. Consequently, if chemotherapy does not eliminate gametocytes, an individual continues to be infectious for several weeks after the clearance of asexual parasites. The work reported here demonstrates that nanomolar concentrations of the proteasome inhibitor epoxomicin effectively kill all stages of intraerythrocytic parasites but do 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%, asexual parasites decreased by 86%, and gametocytes decreased by 77%. Seventy-two hours after treatment, no viable parasites remained in the 100 or 10 nM treatment group. Epoxomicin also blocked oocyst production in the mosquito midgut. In contrast, the cysteine protease inhibitors epoxysuccinyl-L-leucylamido-3-methyl-butane ethyl ester and N-acetyl-L-leucyl-L-leucyl-L-methioninal blocked hemoglobin digestion in early gametocytes but had no effect on later stages. Moreover, once the cysteine protease inhibitor was removed, sexual differentiation resumed. These findings provide strong support for the further development of proteasome inhibitors as antimalaria agents that are effective against asexual, sexual, and mosquito midgut stages of P. falciparum.

* Corresponding author. Mailing address: Loyola University Chicago, Dept. of Biology, Quinlan Life Sciences Building, Rm 317, 6525 N. Sheridan Rd., Chicago, IL 60626. Phone: (773) 508-3631. Fax: (773) 508-3646. E-mail: kwilli4{at}luc.edu

{triangledown} Published ahead of print on 3 August 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4080-4085, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00088-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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