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Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite
BACKGROUND: Malaria continues to be a devastating parasitic disease that causes the death of 2 million individuals annually. The increase in multi-drug resistance together with the absence of an efficient vaccine hastens the need for speedy and comprehensive antimalarial drug discovery and developme...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2008
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391291/ https://www.ncbi.nlm.nih.gov/pubmed/18523554 http://dx.doi.org/10.1371/journal.pone.0002335 |
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author | Prudhomme, Jacques McDaniel, Eric Ponts, Nadia Bertani, Stéphane Fenical, William Jensen, Paul Le Roch, Karine |
author_facet | Prudhomme, Jacques McDaniel, Eric Ponts, Nadia Bertani, Stéphane Fenical, William Jensen, Paul Le Roch, Karine |
author_sort | Prudhomme, Jacques |
collection | PubMed |
description | BACKGROUND: Malaria continues to be a devastating parasitic disease that causes the death of 2 million individuals annually. The increase in multi-drug resistance together with the absence of an efficient vaccine hastens the need for speedy and comprehensive antimalarial drug discovery and development. Throughout history, traditional herbal remedies or natural products have been a reliable source of antimalarial agents, e.g. quinine and artemisinin. Today, one emerging source of small molecule drug leads is the world's oceans. Included among the source of marine natural products are marine microorganisms such as the recently described actinomycete. Members of the genus Salinispora have yielded a wealth of new secondary metabolites including salinosporamide A, a molecule currently advancing through clinical trials as an anticancer agent. Because of the biological activity of metabolites being isolated from marine microorganisms, our group became interested in exploring the potential efficacy of these compounds against the malaria parasite. METHODS: We screened 80 bacterial crude extracts for their activity against malaria growth. We established that the pure compound, salinosporamide A, produced by the marine actinomycete, Salinispora tropica, shows strong inhibitory activity against the erythrocytic stages of the parasite cycle. Biochemical experiments support the likely inhibition of the parasite 20S proteasome. Crystal structure modeling of salinosporamide A and the parasite catalytic 20S subunit further confirm this hypothesis. Ultimately we showed that salinosporamide A protected mice against deadly malaria infection when administered at an extremely low dosage. CONCLUSION: These findings underline the potential of secondary metabolites, derived from marine microorganisms, to inhibit Plasmodium growth. More specifically, we highlight the effect of proteasome inhibitors such as salinosporamide A on in vitro and in vivo parasite development. Salinosporamide A (NPI-0052) now being advanced to phase I trials for the treatment of refractory multiple myeloma will need to be further explored to evaluate the safety profile for its use against malaria. |
format | Text |
id | pubmed-2391291 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-23912912008-06-04 Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite Prudhomme, Jacques McDaniel, Eric Ponts, Nadia Bertani, Stéphane Fenical, William Jensen, Paul Le Roch, Karine PLoS One Research Article BACKGROUND: Malaria continues to be a devastating parasitic disease that causes the death of 2 million individuals annually. The increase in multi-drug resistance together with the absence of an efficient vaccine hastens the need for speedy and comprehensive antimalarial drug discovery and development. Throughout history, traditional herbal remedies or natural products have been a reliable source of antimalarial agents, e.g. quinine and artemisinin. Today, one emerging source of small molecule drug leads is the world's oceans. Included among the source of marine natural products are marine microorganisms such as the recently described actinomycete. Members of the genus Salinispora have yielded a wealth of new secondary metabolites including salinosporamide A, a molecule currently advancing through clinical trials as an anticancer agent. Because of the biological activity of metabolites being isolated from marine microorganisms, our group became interested in exploring the potential efficacy of these compounds against the malaria parasite. METHODS: We screened 80 bacterial crude extracts for their activity against malaria growth. We established that the pure compound, salinosporamide A, produced by the marine actinomycete, Salinispora tropica, shows strong inhibitory activity against the erythrocytic stages of the parasite cycle. Biochemical experiments support the likely inhibition of the parasite 20S proteasome. Crystal structure modeling of salinosporamide A and the parasite catalytic 20S subunit further confirm this hypothesis. Ultimately we showed that salinosporamide A protected mice against deadly malaria infection when administered at an extremely low dosage. CONCLUSION: These findings underline the potential of secondary metabolites, derived from marine microorganisms, to inhibit Plasmodium growth. More specifically, we highlight the effect of proteasome inhibitors such as salinosporamide A on in vitro and in vivo parasite development. Salinosporamide A (NPI-0052) now being advanced to phase I trials for the treatment of refractory multiple myeloma will need to be further explored to evaluate the safety profile for its use against malaria. Public Library of Science 2008-06-04 /pmc/articles/PMC2391291/ /pubmed/18523554 http://dx.doi.org/10.1371/journal.pone.0002335 Text en Prudhomme et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Prudhomme, Jacques McDaniel, Eric Ponts, Nadia Bertani, Stéphane Fenical, William Jensen, Paul Le Roch, Karine Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite |
title | Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite |
title_full | Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite |
title_fullStr | Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite |
title_full_unstemmed | Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite |
title_short | Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite |
title_sort | marine actinomycetes: a new source of compounds against the human malaria parasite |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391291/ https://www.ncbi.nlm.nih.gov/pubmed/18523554 http://dx.doi.org/10.1371/journal.pone.0002335 |
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