Drugs and Transporters in Kinetoplastid Protozoa

Kinetoplastid protozoa express hundreds of membrane transport proteins that allow them to take up nutrients, establish ion gradients, efflux metabolites, translocate compounds from one intracellular compartment to another, and take up or export drugs. The combination of molecular cloning, genetic approaches, and the completed genome projects for Trypanosoma brucei, Leishmania major, and Trypanosoma cruzi have allowed detailed functional analysis of various transporters and predictions about the likely functions of others. Thus many opportunities exist to define the biological and pharmacological properties of parasite transporters whose genes were often difficult to identify in the pregenomic era. A subset of these transporters that are essential for parasite viability could serve as targets for novel drug therapies by identifying compounds that interfere with their uptake functions. Other permeases provide routes for uptake of selectively cytotoxic compounds and can thus be useful for delivery of drugs. Drug resistance may develop in strains where such drug uptake transporters are nonfunctional or in parasites that over-express other permeases that export a drug. A summary of recent work on Leishmania transporters for glucose and for purines is provided as an example of permeases that are being studied in molecular detail.