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Antimicrobial Agents and Chemotherapy, December 2002, p. 3731-3738, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3731-3738.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Mireille Basselin,1,{dagger} Hubert Denise,2 Graham H. Coombs,1 and Michael P. Barrett1*

Division of Infection & Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ,1 Wellcome Centre for Molecular Parasitology, The Anderson College, University of Glasgow, Glasgow G11 6NU, United Kingdom2

Received 24 October 2001/ Returned for modification 5 May 2002/ Accepted 12 August 2002

The uptake of [3H]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 Vmax, 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.

* Corresponding author. Mailing address: Institute of Biomedical and Life Sciences, Division of Infection & Immunity, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, United Kingdom. Phone: 44 141 330 6904. E-mail: m.barrett{at}bio.gla.ac.uk.

{dagger} Present address: Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda MD 20892-1582.

Antimicrobial Agents and Chemotherapy, December 2002, p. 3731-3738, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3731-3738.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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