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Antimicrobial Agents and Chemotherapy, April 2009, p. 1403-1410, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01215-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Amiodarone Destabilizes Intracellular Ca2+ Homeostasis and Biosynthesis of Sterols in Leishmania mexicana{triangledown}

Xenón Serrano-Martín,1,2 Yael García-Marchan,1,2 Alexis Fernandez,3 Noris Rodriguez,3 Hector Rojas,4 Gonzalo Visbal,5 and Gustavo Benaim1,2*

Centro de Biociencias y Medicina Molecular, Instituto de Estudios Avanzados, Caracas, Venezuela,1 Instituto de Biología Experimental, Facultad de Ciencias, Universidad Central de Venezuela (UCV), Caracas, Venezuela,2 Instituto de Biomedicina (UCV),3 Centro de Biofísica y Bioquímica,4 Centro de Química, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela5

Received 12 September 2008/ Returned for modification 19 November 2008/ Accepted 8 January 2009

Leishmaniasis represents a serious public health problem worldwide. The first line of treatment is based on glucantime and pentostan, which generate toxic effects in treated patients. We have recently shown that amiodarone, frequently used as an antiarrhythmic, possesses activity against Trypanosoma cruzi through the disruption of mitochondrial Ca2+ homeostasis and the inhibition of parasite ergosterol biosynthesis, specifically at the level of oxidosqualene cyclase activity (G. Benaim, J. Sanders, Y. Garcia-Marchan, C. Colina, R. Lira, A. Caldera, G. Payares, C. Sanoja, J. Burgos, A. Leon-Rossell, J. Concepcion, A. Schijman, M. Levin, E. Oldfield, and J. Urbina, J. Med. Chem. 49:892-899, 2006). Here we show that at therapeutic concentrations, amiodarone has a profound effect on the viability of Leishmania mexicana promastigotes. Additionally, its effect on the viability of the parasite was greater against intracellular amastigotes than against promastigotes, and it did not affect the host cell. Using fluorimetric and confocal microscopy techniques, we also demonstrated that the mechanism of action of amiodarone was related to the disruption of intracellular Ca2+ homeostasis through a direct action not only on the mitochondria but also on the acidocalcisomes. On the other hand, analysis of the free sterols in promastigotes incubated with amiodarone showed that this drug also affected the biosynthesis of 5-dehydroepisterol, which results in squalene accumulation, thus suggesting that amiodarone inhibits the squalene epoxidase activity of the parasite. Taken together, the results obtained in the present work point to a more general effect of amiodarone in trypanosomatids, opening potential therapeutic possibilities for this infectious disease.

* Corresponding author. Mailing address: Centro de Biociencias y Medicina Molecular, Instituto de Estudios Avanzados, Carretera Nacional Hoyo de la Puerta, Sartenejas, Baruta, Caracas, Venezuela. Phone: 58-212-903-5120. Fax: 58-212-903-5118. E-mail: gbenaim{at}idea.gob.ve

{triangledown} Published ahead of print on 21 January 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1403-1410, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01215-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Serrano-Martin, X., Payares, G., De Lucca, M., Martinez, J. C., Mendoza-Leon, A., Benaim, G. (2009). Amiodarone and Miltefosine Act Synergistically against Leishmania mexicana and Can Induce Parasitological Cure in a Murine Model of Cutaneous Leishmaniasis. Antimicrob. Agents Chemother. 53: 5108-5113 [Abstract] [Full Text]  


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