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Antimicrobial Agents and Chemotherapy, July 2005, p. 2857-2864, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2857-2864.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

3-Aminooxy-1-Aminopropane and Derivatives Have an Antiproliferative Effect on Cultured Plasmodium falciparum by Decreasing Intracellular Polyamine Concentrations

Department of Biochemistry, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, D-20359 Hamburg, Germany,¹ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia,² Institute of Biomedical and Life Sciences, Infection and Immunity, University of Glasgow, Glasgow G12 8QQ, United Kingdom³

Received 16 September 2004/ Returned for modification 13 October 2004/ Accepted 3 March 2005

The intraerythrocytic development of Plasmodium falciparum correlates with increasing levels of the polyamines putrescine, spermidine, and spermine in the infected red blood cells; and compartmental analyses revealed that the majority is associated with the parasite. Since depletion of cellular polyamines is a promising strategy for inhibition of parasite proliferation, new inhibitors of polyamine biosynthesis were tested for their antimalarial activities. The ornithine decarboxylase (ODC) inhibitor 3-aminooxy-1-aminopropane (APA) and its derivatives CGP 52622A and CGP 54169A as well as the S-adenosylmethionine decarboxlyase (AdoMetDC) inhibitors CGP 40215A and CGP 48664A potently affected the bifunctional P. falciparum ODC-AdoMetDC, with K_i values in the low nanomolar and low micromolar ranges, respectively. Furthermore, the agents were examined for their in vitro plasmodicidal activities in 48-h incubation assays. APA, CGP 52622A, CGP 54169A, and CGP 40215A were the most effective, with 50% inhibitory concentrations below 3 µM. While the effects of the ODC inhibitors were completely abolished by the addition of putrescine, growth inhibition by the AdoMetDC inhibitor CGP 40215A could not be antagonized by putrescine or spermidine. Moreover, CGP 40215A did not affect the cellular polyamine levels, indicating a mechanism of action against P. falciparum independent of polyamine synthesis. In contrast, the ODC inhibitors led to decreased cellular putrescine and spermidine levels in P. falciparum, supporting the fact that they exert their antimalarial activities by inhibition of the bifunctional ODC-AdoMetDC.

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