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Antimicrobial Agents and Chemotherapy, February 2007, p. 528-534, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01055-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antileishmanial Effect of 3-Aminooxy-1-Aminopropane Is Due to Polyamine Depletion

School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India,¹ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia,² Department of Experimental Medical Science, Lund University, Lund, Sweden,³ Department of Molecular Biology, Umeå University, S-901 87 Umeå, Sweden,⁴ Department of Pharmacology, Institute of Postgraduate Medical Education & Research, 244B Acharya JC Bose Road, Kolkata 700 02, India⁵

Received 22 August 2006/ Returned for modification 19 September 2006/ Accepted 31 October 2006

The polyamines putrescine, spermidine, and spermine are organic cations that are required for cell growth and differentiation. Ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the polyamine biosynthetic pathway, catalyzes the conversion of ornithine to putrescine. As the polyamine biosynthetic pathway is essential for the growth and survival of Leishmania donovani, the causative agent of visceral leishmaniasis, inhibition of the pathway is an important leishmaniacidal strategy. In the present study, we examined for the first time the effects of 3-aminooxy-1-aminopropane (APA), an ODC inhibitor, on the growth of L. donovani. APA inhibited the growth of both promastigotes in vitro and amastigotes in the macrophage model, with the 50% inhibitory concentrations being 42 and 5 µM, respectively. However, concentrations of APA up to 200 µM did not affect the viability of macrophages. The effects of APA were completely abolished by the addition of putrescine or spermidine. APA induced a significant decrease in ODC activity and putrescine, spermidine, and trypanothione levels in L. donovani promastigotes. Parasites were transfected with an episomal ODC construct, and these ODC overexpressers exhibited significant resistance to APA and were concomitantly resistant to sodium antimony gluconate (Pentostam), indicating a role for ODC overexpression in antimonial drug resistance. Clinical isolates with sodium antimony gluconate resistance were also found to overexpress ODC and to have significant increases in putrescine and spermidine levels. However, no increase in trypanothione levels was observed. The ODC overexpression in these clinical isolates alleviated the antiproliferative effects of APA. Collectively, our results demonstrate that APA is a potent inhibitor of L. donovani growth and that its leishmaniacidal effect is due to inhibition of ODC.

Published ahead of print on 13 November 2006.

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