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Antimicrobial Agents and Chemotherapy, May 2003, p. 1529-1535, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1529-1535.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The In Vivo Susceptibility of Leishmania donovani to Sodium Stibogluconate Is Drug Specific and Can Be Reversed by Inhibiting Glutathione Biosynthesis

K. C. Carter,1* S. Sundar,2 C. Spickett,3 O. C. Pereira,4 and A. B. Mullen5

Department of Immunology,1 Department of Bioscience,3 Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, United Kingdom,5 Department of Medicine, Institute of Medical Sciences, Baranas Hindu University, Varansi, India,2 Faculty of Pharmacy, Porto University, Porto, Portugal4

Received 21 October 2002/ Returned for modification 27 November 2002/ Accepted 27 January 2003

Resistance to pentavalent antimonial (Sbv) agents such as sodium stibogluconate (SSG) is creating a major problem in the treatment of visceral leishmaniasis. In the present study the in vivo susceptibilities of Leishmania donovani strains, typed as SSG resistant (strain 200011) or SSG sensitive (strain 200016) on the basis of their responses to a single SSG dose of 300 mg of Sbv/kg of body weight, to other antileishmanial drugs were determined. In addition, the role of glutathione in SSG resistance was investigated by determining the influence on SSG treatment of concomitant treatment with a nonionic surfactant vesicle formulation of buthionine sulfoximine (BSO), a specific inhibitor of the enzyme {gamma}-glutamylcysteine synthetase which is involved in glutathione biosynthesis, and SSG, on the efficacy of SSG treatment. L. donovani strains that were SSG resistant (strain 200011) and SSG sensitive (strain 200016) were equally susceptible to in vivo treatment with miltefosine, paromomycin and amphotericin B (Fungizone and AmBisome) formulations. Combined treatment with SSG and vesicular BSO significantly increased the in vivo efficacy of SSG against both the 200011 and the 200016 L. donovani strains. However, joint treatment that included high SSG doses was unexpectedly associated with toxicity. Measurement of glutathione levels in the spleens and livers of treated mice showed that the ability of the combined therapy to inhibit glutathione levels was also dependent on the SSG dose used and that the combined treatment exhibited organ-dependent effects. The SSG resistance exhibited by the L. donovani strains was not associated with cross-resistance to other classes of compounds and could be reversed by treatment with an inhibitor of glutathione biosynthesis, indicating that clinical resistance to antimonial drugs should not affect the antileishmanial efficacies of alternative drugs. In addition, it should be possible to identify a treatment regimen that could reverse antimony resistance.

* Corresponding author. Mailing address: Department of Immunology, SIBS, University of Strathclyde, 31 Taylor St., Glasgow G4 ONR, United Kingdom. Phone: 0141-552-4400. Fax: 0141-548-3427. E-mail: K.carter{at}strath.ac.uk.

Antimicrobial Agents and Chemotherapy, May 2003, p. 1529-1535, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1529-1535.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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