ABC multidrug transporters in schistosomes and other parasitic flatworms

Abstract

Schistosomiasis, a neglected tropical disease affecting hundreds of millions, is caused by parasitic flatworms of the genus Schistosoma. Treatment and control of schistosomiasis relies almost exclusively on a single drug, praziquantel (PZQ), a dangerous situation for a disease of this magnitude. Though PZQ is highly effective overall, it has drawbacks, and reports of worms showing PZQ resistance, either induced in the laboratory or isolated from the field, are disconcerting. Multidrug transporters underlie multidrug resistance (MDR), a phenomenon in which resistance to a single drug is accompanied by unexpected cross-resistance to several structurally unrelated compounds. Some of the best studied multidrug transporters are members of the ancient and very large ATP-binding cassette (ABC) superfamily of efflux transporters. ABC multidrug transporters such as P-glycoprotein (Pgp; ABCB1) are also associated with drug resistance in parasites, including helminths such as schistosomes. In addition to their association with drug resistance, however, ABC transporters also function in a wide variety of physiological processes in metazoans. In this review, we examine recent studies that help define the role of schistosome ABC transporters in regulating drug susceptibility, and in normal schistosome physiology, including reproduction and excretory activity. We postulate that schistosome ABC transporters could be useful targets for compounds that enhance the effectiveness of current therapeutics as well as for agents that act as antischistosomals on their own.

Keywords: ABC transporters; Drug resistance; P-Glycoprotein; Schistosoma.

Fig. 1. Structure of ABC multidrug transporters

A. Predicted domain arrangement of ABC transporters found in the human genome. Shown are the arrangement of transmembrane domains (TMD) and nucleotide binding domains (NBD) found in human ABC transporters. The TMD₀ domain is found in some members of the ABCC sub-family. Letters on to the right of the cartoon designate ABC sub-families in which that predicted domain topology is found. Figure adapted from [41] and [35]. B. Homology model of SMDR2. SMDR2 was modeled against C. elegans Pgp (pdb 4F4C; [55]) using ESyPred3D (http://www.fundp.ac.be/sciences/biologie/urbm/bioinfo/esypred/) [113]. Residues at the N-terminus (1–4), linker (609–656), and C-terminus (1243–1255) were not included in the final model. The figure was generated using the program PyMOL (http://www.pymol.org/). NBD1 and NBD2 designate the nucleotide binding domains, and the numbers 1–12 indicate the helical transmembrane-spanning segments. Domain 1 is in blue; domain 2 is in orange. C. Model for binding and transport of substrate by Pgp. Substrate (circle) partitions from outside the cell into the inner leaflet of the lipid bilayer, where, according to the hydrophobic “vacuum cleaner” model, it enters the drug-binding pocket of Pgp. ATP binding to the NBDs produces a conformational change that results in presentation of the substrate to the outer leaflet or extracellular space.