This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carter, K. C. Articles by Mullen, A. B. Search for Related Content PubMed PubMed Citation Articles by Carter, K. C. Articles by Mullen, A. B.

 Previous Article  |  Next Article 

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 -Glutamylcysteine Synthetase

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 -glutamylcysteine synthetase (-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 -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 -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 -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 -GCS expression was not obtained when using tissues from infected mice. In this case -GCS expression was organ and strain dependent for both the host and the parasite, indicating that environmental conditions have a profound effect on -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.

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]