Skip to main content Accessibility help

Sodium stibogluconate resistance in Leishmania donovani correlates with greater tolerance to macrophage antileishmanial responses and trivalent antimony therapy

  • K. C. CARTER (a1), S. HUTCHISON (a1), A. BOITELLE (a1), H. W. MURRAY (a1) (a2), S. SUNDAR (a3) and A. B. MULLEN (a4)...


Co-treatment of mice infected with different strains of Leishmania donovani with a non-ionic surfactant vesicle formulation of buthionine sulfoximine (BSO-NIV), and sodium stibogluconate (SSG), did not alter indicators of Th1 or Th2 responses but did result in a significant strain-independent up-regulation of IL6 and nitrite levels by stimulated splenocytes from treated mice compared to controls. The efficacy of BSO-NIV/SSG treatment was dependent on the host being able to mount a respiratory burst indicating that macrophages are important in controlling the outcome of treatment. In vitro studies showed that SSG resistance was associated with a greater resistance to killing by activated macrophages, treatment with hydrogen peroxide or potassium antimony tartrate. Longitudinal studies showed that a SSG resistant (SSG-R) strain was more virulent than a SSG susceptible (SSG-S) strain, resulting in significantly higher parasite burdens by 4 months post-infection. These results indicate that SSG exposure may favour the emergence of more virulent strains.


Corresponding author

Department of Immunology, SIBS, University of Strathclyde, 31 Taylor Street, Glasgow G4 0NR, UK. Tel: +44 0141 548 3823. Fax: +44 0141 548 3427. E-mail:


Hide All


Bailey, H. H. ( 1998). L-S, R-buthionine sulfoximine: historical development and clinical issues. Chemico-Biological Interactions 111–112, 239254.
Banduwardene, R, Mullen, A. B. and Carter, K. C. ( 1997). Immune responses of Leishmania donovani infected BALB/c mice following treatment with free and vesicular sodium stibogluconate formulations. International Journal of Immunopharmacology 19, 195203.
Barr, S. D. and Gedamu, L. ( 2003). Role of peroxidoxins in Leishmania chagasi survival. Evidence of an enzymatic defense against nitrosative stress. Journal of Biological Chemistry 278, 1081610823.
Carter, K. C., Baillie, A. J., Alexander, J. and Dolan, T. F. ( 1988). The therapeutic effect of sodium stibogluconate in the BALB/c mice infected with L. donovani is organ dependent. 1988. Journal of Pharmacy and Pharmacology 40, 370373.
Carter, K. C., Mullen, A. B., Sundar, S. and Kenney, R. T. ( 2001). The efficacy of vesicular and free sodium stibogluconate formulations against clinical isolates of Leishmania donovani. Antimicrobrobial Agents and Chemotherapy 45, 355359.
Carter, K. C., Sundar, S., Spickett, C., Pereira, O. C. and Mullen, A. B. ( 2003). The in vivo susceptibility of Leishmania donovani to sodium stibogluconate is drug specific and can be reversed by inhibiting glutathione biosynthesis. Antimicrobrobial Agents and Chemotherapy 47, 15291535.
Croft, S. L. and Coombs, G. H. ( 2003). Leishmaniasis – current chemotherapy and recent advances in the search for novel drugs. Trends in Parasitology 19, 502508.
Engwerda, C. R. and Kaye, P. M. ( 1999). Organ-specific immune responses associated with infectious disease. Immunology Today 2000 21, 7378.
Gebel, T. ( 1997). Arsenic and antimony: comparative approach on mechanistic toxicology. Chemico-biological Interactions 107, 131144.
Goodwin, L. C. and Page, J. E. ( 1943). A study of the excretion of inorganic antimonials using a polarographic procedure. Biochemistry 22, 236240.
Goyal, N., Roy, U. and Rastogi, A. K. ( 1996). Relative resistance of promastigotes of a virulent and an avirulent strain of Leishmania donovani to hydrogen peroxide. Free Radical Biology and Medicine 21, 683689.
Grondin, K., Haimeur, A., Mukhopadhyay, R., Rosen, B. P. and Ouellette, M. ( 1997). Co-amplification of the gamma-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO Journal 16, 30573065.
Haddad, J. J. ( 2002). Oxygen-sensing mechanisms and the regulation of redox-responsive transcription factors in development and pathophysiology. Respiratory Research 3, 2653.
Haddad, J. J., Saade, N. E. and Safieh-Garabedian, B. ( 2002). Redox regulation of TNF-alpha biosynthesis: augmentation by irreversible inhibition of gamma-glutamylcysteine synthetase and the involvement of an I kappaB-alpha/NF-kappaB-independent pathway in alveolar epithelial cells. Cell Signal 14, 211218.
Haimeur, A. and Ouellette, M. ( 1998). Gene amplification in Leishmania tarentolae selected for resistance to sodium stibogluconate. Antimicrobial Agents and Chemotherapy 42, 16891694.
Kapoor, P., Sachdev, M. and Madhubala, R. ( 2000). Inhibition of glutathione synthesis as a chemotherapeutic strategy for leishmaniasis. Tropical Medicine and International Health 5, 438442.
Legare, D., Papadoulou, B., Roy, G., Mukhopadhyay, R., Haimeur, A., Dey, S., Grondin, K., Brochu, C., Rosen, B. P. and Ouellette, M. ( 1997). Efflux systems and increased trypanothionine levels in arsenite-resistant Leishmania. Experimental Parasitology 87, 275282.
Murata, Y., Shimamura, T. and Hamuro, J. ( 2002). The polarization of T(h)1/T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. International Immunology 14, 201212.
Murray, H. W. and Delph-Etienne, S. ( 2000). Roles of endogenous gamma interferon and macrophage microbicidal mechanisms in host response to chemotherapy in experimental visceral leishmaniasis. Infection and Immunity 68, 288293.
Murray, H. W. and Nathan, C. F. ( 1999). Macrophage microbial mechanism in vivo: reactive nitrogen versus oxygen intermediates in the killing of intracellular visceral leishmaniasis. Journal of Experimental Medicine 189, 741746.
Sereno, D., Cavaleyra, M., Zemzoumi, K., Maquaire, S., Ouaissi, A. and Lemesre, J. L. ( 1998). Axenically grown amastigotes of Leishmania infantum used as an in vitro model to investigate the pentavalent antimony mode of action. Antimicrobial Agents and Chemotherapy 42, 30973102.
Sudhandiran, G. and Shaha, C. ( 2003). Antimonial induced increase in intracellular Ca2+ through non-selective cation channels in the host and the parasite is responsible for apoptosis of intracellular Leishmania donovani amastigotes. Journal of Biological Chemistry 278, 2512025132.
Wyllie, S., Cunningham, M. L. and Fairlamb, A. H. ( 2004). Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani. Journal of Biological Chemistry 279, 3992539932.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed