Symmetrical choline-derived dications display strong anti-kinetoplastid activity
| Autor: | Harry P. de Koning, Roger Escale, Abdulsalam A. M. Alkhaldi, Terry K. Smith, Henri Vial, Mohammed I. Al-Salabi, Hasan M. S. Ibrahim, Neils B. Quashie, Nasser El Sabbagh |
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| Přispěvatelé: | Institute of Infection, Immunity and Inflammation, University of Glasgow, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), BMS, University of St Andrews [Scotland], Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1) |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Microbiology (medical)
Cations Divalent Leishmania mexicana Trypanosoma brucei brucei Phospholipid Antiprotozoal Agents DNA Fragmentation Trypanosoma brucei 03 medical and health sciences chemistry.chemical_compound choline parasitic diseases lipid metabolism Choline Pharmacology (medical) Cyclic adenosine monophosphate Fragmentation (cell biology) leishmaniasis 030304 developmental biology Original Research protozoan parasite Pharmacology Membrane Potential Mitochondrial 0303 health sciences biology 030306 microbiology [CHIM.ORGA]Chemical Sciences/Organic chemistry biology.organism_classification 3. Good health Mitochondria Choline transporter Infectious Diseases chemistry Biochemistry DNA fragmentation |
| Zdroj: | Journal of Antimicrobial Chemotherapy Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), 2011, 66, pp.111-125. ⟨10.1093/jac/dkq401⟩ |
| ISSN: | 0305-7453 1460-2091 |
| DOI: | 10.1093/jac/dkq401⟩ |
| Popis: | International audience; OBJECTIVES: to investigate the anti-kinetoplastid activity of choline-derived analogues with previously reported antimalarial efficacy. METHODS: from an existing choline analogue library, seven antimalarial compounds, representative of the first-, second- and third-generation analogues previously developed, were assessed for activity against Trypanosoma and Leishmania spp. Using a variety of techniques, the effects of choline analogue exposure on the parasites were documented and a preliminary investigation of their mode of action was performed. RESULTS: the activities of choline-derived compounds against Trypanosoma brucei and Leishmania mexicana were determined. The compounds displayed promising anti-kinetoplastid activity, particularly against T. brucei, to which 4/7 displayed submicromolar EC(50) values for the wild-type strain. Low micromolar concentrations of most compounds cleared trypanosome cultures within 24-48 h. The compounds inhibit a choline transporter in Leishmania, but their entry may not depend only on this carrier; T. b. brucei lacks a choline carrier and the mode of uptake remains unclear. The compounds had no effect on the overall lipid composition of the cells, cell cycle progression or cyclic adenosine monophosphate production or short-term effects on intracellular calcium levels. However, several of the compounds, displayed pronounced effects on the mitochondrial membrane potential; this action was not associated with production of reactive oxygen species but rather with a slow rise of intracellular calcium levels and DNA fragmentation. CONCLUSIONS: the choline analogues displayed strong activity against kinetoplastid parasites, particularly against T. b. brucei. In contrast to their antimalarial activity, they did not act on trypanosomes by disrupting choline salvage or phospholipid metabolism, instead disrupting mitochondrial function, leading to chromosomal fragmentation. |
| Databáze: | OpenAIRE |
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