Resistance to Pentamidine in Leishmania mexicana Involves Exclusion of the Drug from the Mitochondrion

Author:

Basselin Mireille1,Denise Hubert2,Coombs Graham H.1,Barrett Michael P.1

Affiliation:

1. Division of Infection & Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ

2. Wellcome Centre for Molecular Parasitology, The Anderson College, University of Glasgow, Glasgow G11 6NU, United Kingdom

Abstract

ABSTRACT The uptake of [ 3 H]pentamidine into wild-type and drug-resistant strains of Leishmania mexicana was compared. Uptake was carrier mediated. Pentamidine-resistant parasites showed cross-resistance to other toxic diamidine derivatives. A substantial decrease in accumulation of the drug accompanied the resistance phenotype, although the apparent affinity for pentamidine by its carrier was not altered when initial uptake velocity was measured. The apparent V max , however, was reduced. An efflux of pentamidine could be measured in both wild-type and resistant cells. Only a relatively small proportion of the total accumulated pentamidine was available for efflux in wild-type cells, while in resistant cells the majority of loaded pentamidine was available for release. Pharmacological reagents which diminish the mitochondrial membrane potential reduced pentamidine uptake in wild-type parasites, and the mitochondrial membrane potential was shown to be reduced in resistant cells. A fluorescent analogue of pentamidine, 4′,6′-diamidino-2-phenylindole, accumulated in the kinetoplast of wild-type but not resistant parasites. These data together indicate that diamidine drugs accumulate in the Leishmania mitochondrion and that the development of the resistance phenotype is accompanied by lack of mitochondrial accumulation of the drug and its exclusion from the parasites.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference61 articles.

1. Aggarwal, P., R. Handa, S. Singh, and J. P. Wali. 1999. Kala-azar: new developments in diagnosis and treatment. Indian J. Pediatr.66:63-71.

2. Amato, V., J. Amato, A. Nicodemo, D. Uip, V. Amato-Neto, and M. Duarte. 1998. Treatment of mucocutaneous leishmaniasis with pentamidine isethionate. Ann. Dermatol. Venérelo.125:492-495.

3. Arato-Oshilma, T., H. Matsui, A. Wakizaka, and H. Homareda. 1996. Mechanism responsible for oligomycin-induced occlusion of Na+ within Na/K-ATPase. J. Biol. Chem.271:25604-25610.

4. Bailly, C., L. Dassonneville, C. Carrasco, D. Lucas, A. Kumar, D. W. Boykin, and W. D. Wilson. 1999. Relationships between topoisomerase II inhibition, sequence-specificity and DNA binding mode of dicationic diphenylfuran derivatives. Anticancer Drug Design14:47-60.

5. Barrett, M. P., Z. Q. Zhang, H. Denise, C. Giroud, and T. Baltz. 1995. A diamidine-resistant Trypanosoma equiperdum clone contains a P2 purine transporter with reduced substrate affinity. Mol. Biochem. Parasitol.73:223-229.

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