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Antimicrobial Agents and Chemotherapy, May 2004, p. 1534-1540, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1534-1540.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Fungus-Elicited Metabolites from Plants as an Enriched Source for New Leishmanicidal Agents: Antifungal Phenyl-Phenalenone Phytoalexins from the Banana Plant (Musa acuminata) Target Mitochondria of Leishmania donovani Promastigotes

Juan Román Luque-Ortega,1 Silvia Martínez,2 José María Saugar,1 Laura R. Izquierdo,3 Teresa Abad,3 Javier G. Luis,3 José Piñero,2 Basilio Valladares,2 and Luis Rivas1*

Centro de Investigaciones Biológicas, E-28040 Madrid,1 Departamento de Parasitología, Facultad de Farmacia, Universidad de La Laguna, E-38206 La Laguna-Tenerife,2 Instituto de Bio-Orgánica A.G. González, E-38206 La Laguna-Tenerife, Spain3

Received 31 July 2003/ Returned for modification 25 November 2003/ Accepted 30 January 2004

Two antifungal phenyl-phenalenone phytoalexins isolated from the banana plant (Musa acuminata) elicited with the fungus Fusarium oxysporum, together with a methoxy derivative of one of them and two epoxide precursors of their chemical synthesis, were tested for leishmanicidal activity on Leishmania donovani promastigotes and L. infantum amastigotes. Drugs inhibited proliferation of both forms of the parasite with a 50% lethal concentration range between 10.3 and 68.7 µg/ml. Their lethal mechanism was found linked to the respiratory chain by a systematic approach, including electron microscopy, measurement of the oxygen consumption rate on digitonin-permeabilized promastigotes, and enzymatic assays on a mitochondrial enriched fraction. Whereas the whole set of compounds inhibited the activity of fumarate reductase in the mitochondrial fraction (50% effective concentration [EC50] between 33.3 and 78.8 µg/ml) and on purified enzyme (EC50 = 53.3 to 115 µg/ml), inhibition for succinate dehydrogenase was only observed for the two phytoalexins with the highest leishmanicidal activity: anigorufone and its natural analogue 2-methoxy-9-phenyl-phenalen-1-one (EC50 = 33.5 and 59.6 µg/ml, respectively). These results provided a new structural motif, phenyl-phenalenone, as a new lead for leishmanicidal activity, and support the use of plant extracts enriched in antifungal phytoalexins, synthesized under fungal challenge, as a more rational and effective strategy to screen for new plant leishmanicidal drugs.

* Corresponding author. Mailing address: Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, E-28040, Madrid, Spain. Phone: 34-918373112, ext. 4234. Fax: 34-915627518. E-mail: luis_rivas{at}cib.csic.es.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1534-1540, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1534-1540.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Luque-Ortega, J. R., Hof, W. v., Veerman, E. C. I., Saugar, J. M., Rivas, L. (2008). Human antimicrobial peptide histatin 5 is a cell-penetrating peptide targeting mitochondrial ATP synthesis in Leishmania. FASEB J. 22: 1817-1828 [Abstract] [Full Text]  
  • Luque-Ortega, J. R., Rivas, L. (2007). Miltefosine (Hexadecylphosphocholine) Inhibits Cytochrome c Oxidase in Leishmania donovani Promastigotes. Antimicrob. Agents Chemother. 51: 1327-1332 [Abstract] [Full Text]  


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