Antileishmanial effect of 3-aminooxy-1-aminopropane is due to polyamine depletion.
(2007) In Antimicrobial Agents and Chemotherapy 51. p.528-534- Abstract
- 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,... (More)
- 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 mu M, respectively. However, concentrations of APA up to 200 mu M 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/163263
- author
- Singh, Sushma ; Mukherjee, Angana ; Khomutov, Alex R ; Persson, Lo LU ; Heby, Olle ; Chatterjee, Mitali and Madhubala, Rentala
- organization
- publishing date
- 2007
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Antimicrobial Agents and Chemotherapy
- volume
- 51
- pages
- 528 - 534
- publisher
- American Society for Microbiology
- external identifiers
-
- wos:000243900600018
- scopus:33846575594
- ISSN
- 1098-6596
- DOI
- 10.1128/AAC.01055-06
- language
- English
- LU publication?
- yes
- id
- 0a6980c6-2927-44a4-848e-30249e9e2130 (old id 163263)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17101681&dopt=Abstract
- date added to LUP
- 2016-04-01 16:05:15
- date last changed
- 2022-02-12 19:42:40
@article{0a6980c6-2927-44a4-848e-30249e9e2130,
abstract = {{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 mu M, respectively. However, concentrations of APA up to 200 mu M 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.}},
author = {{Singh, Sushma and Mukherjee, Angana and Khomutov, Alex R and Persson, Lo and Heby, Olle and Chatterjee, Mitali and Madhubala, Rentala}},
issn = {{1098-6596}},
language = {{eng}},
pages = {{528--534}},
publisher = {{American Society for Microbiology}},
series = {{Antimicrobial Agents and Chemotherapy}},
title = {{Antileishmanial effect of 3-aminooxy-1-aminopropane is due to polyamine depletion.}},
url = {{http://dx.doi.org/10.1128/AAC.01055-06}},
doi = {{10.1128/AAC.01055-06}},
volume = {{51}},
year = {{2007}},
}