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Antimicrobial Agents and Chemotherapy, January 2006, p. 88-95, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.88-95.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Resistance of Leishmania donovani to Sodium Stibogluconate Is Related to the Expression of Host and Parasite {gamma}-Glutamylcysteine Synthetase

K. C. Carter,1* S. Hutchison,1 F. L. Henriquez,1 D. Légaré,2 M. Ouellette,2 C. W. Roberts,1 and A. B. Mullen3

Department of Immunology, University of Strathclyde, Glasgow, United Kingdom,1 Centre de Recherche en Infectiologie du Centre de Recherche du CHUL, Université Laval, Québec, Canada,2 Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, United Kingdom3

Received 28 July 2005/ Returned for modification 25 August 2005/ Accepted 12 September 2005

Sequencing studies showed that the {gamma}-glutamylcysteine synthetase ({gamma}-GCS) heavy chain genes from sodium stibogluconate (SSG)-resistant (SSG-R) and SSG-susceptible (SSG-S) Leishmania donovani strains were identical, indicating that SSG resistance was related to quantitative differences in {gamma}-GCS expression rather than gene interstrain polymorphisms. In vitro infection of murine macrophages with the SSG-R strain, but not the SSG-S strain, down regulated expression of host {gamma}-GCS, which would result in a reduction in intramacrophage glutathione (GSH) levels and promote an oxidative intramacrophage environment. This would inhibit, or minimize, the reduction of SSG pentavalent antimony to its more toxic trivalent form. Macrophage studies showed that the SSG-R strain expressed higher levels of {gamma}-GCS compared to the SSG-S strain, which would result in higher GSH levels, giving increased protection against oxidative stress and facilitating SSG efflux. However a similar differential effect on host and parasite {gamma}-GCS expression was not obtained when using tissues from infected mice. In this case {gamma}-GCS expression was organ and strain dependent for both the host and the parasite, indicating that environmental conditions have a profound effect on {gamma}-GCS expression. Consistent with the proposed mechanism from in vitro studies, increasing tissue GSH levels in the presence of SSG by cotreatment of L. donovani-infected mice with SSG solution and GSH incorporated into nonionic surfactant vesicles was more effective in reducing liver, spleen, and bone marrow parasite burdens than monotherapy with SSG. Together, these results indicate that SSG resistance is associated with manipulation of both host and parasite GSH levels by L. donovani.

* Corresponding author. Mailing address: Department of Immunology, SIBS, University of Strathclyde, 31 Taylor Street, Glasgow G4 0NR, United Kingdom. Phone: 44-141-548-3823. Fax: 44-141-548-3427. E-mail: k.carter{at}strath.ac.uk.

Antimicrobial Agents and Chemotherapy, January 2006, p. 88-95, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.88-95.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • El Fadili, K., Imbeault, M., Messier, N., Roy, G., Gourbal, B., Bergeron, M., Tremblay, M. J., Legare, D., Ouellette, M. (2008). Modulation of Gene Expression in Human Macrophages Treated with the Anti-Leishmania Pentavalent Antimonial Drug Sodium Stibogluconate. Antimicrob. Agents Chemother. 52: 526-533 [Abstract] [Full Text]  
  • MITTAL, M. K., RAI, S., ASHUTOSH, , RAVINDER, , GUPTA, S., SUNDAR, S., GOYAL, N. (2007). CHARACTERIZATION OF NATURAL ANTIMONY RESISTANCE IN LEISHMANIA DONOVANI ISOLATES. Am J Trop Med Hyg 76: 681-688 [Abstract] [Full Text]  
  • Ashutosh, , Sundar, S., Goyal, N. (2007). Molecular mechanisms of antimony resistance in Leishmania. J Med Microbiol 56: 143-153 [Abstract] [Full Text]  


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