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Antimicrobial Agents and Chemotherapy, October 1998, p. 2731-2738, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Proteasome Inhibitors Block Development of Plasmodium spp.

Soren M. Gantt,¹ Joon Mo Myung,² Marcelo R. S. Briones,³ Wei Dong Li,⁴ E. J. Corey,⁴ Satoshi Omura,⁵ Victor Nussenzweig,¹ and Photini Sinnis^2,*

Department of Pathology¹ and Department of Medical and Molecular Parasitology,² NYU Medical Center, New York, New York 10016; Disciplina Biologia Celular, Escola Paulista de Medicina, Sao Paulo CEP 04023-062, Brazil³; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138⁴; and School of Pharmaceutical Sciences, Kitasato University and The Kitasato Institute, Tokyo 108, Japan⁵

Received 29 May 1998/Returned for modification 29 June 1998/Accepted 3 August 1998

Proteasomes degrade most of the proteins inside eukaryotic cells, including transcription factors and regulators of cell cycle progression. Here we show that nanomolar concentrations of lactacystin, a specific irreversible inhibitor of the 20S proteasome, inhibit development of the exoerythrocytic and erythrocytic stages of the malaria parasite. Although lactacystin-treated Plasmodium berghei sporozoites are still invasive, their development into exoerythrocytic forms (EEF) is inhibited in vitro and in vivo. Erythrocytic schizogony of P. falciparum in vitro is also profoundly inhibited when drug treatment of the synchronized parasites is prior, but not subsequent, to the initiation of DNA synthesis, suggesting that the inhibitory effect of lactacystin is cell cycle specific. Lactacystin reduces P. berghei parasitemia in rats, but the therapeutic index is very low. Along with other studies showing that lactacystin inhibits stage-specific transformation in Trypanosoma and Entamoeba spp., these findings highlight the potential of proteasome inhibitors as drugs for the treatment of diseases caused by protozoan parasites.

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^* Corresponding author. Mailing address: NYU Medical Center, Department of Medical and Molecular Parasitology, 341 East 25th St., New York, NY 10016. Phone: (212) 263-5346. Fax: (212) 263-8179. E-mail: photini.sinnis{at}med.nyu.edu.

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Antimicrobial Agents and Chemotherapy, October 1998, p. 2731-2738, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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