The ABCs of multidrug resistance in malaria Jan B. Koenderink 1 , Reginald A. Kavishe 2 , Sanna R. Rijpma 1 and Frans G.M. Russel 1 1 Department of Pharmacology and Toxicology 149, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands 2 Kilimanjaro Christian Medical College of Tumaini University, P.O. Box 2240, Moshi, Tanzania Expanding drug resistance could become a major pro- blem in malaria treatment, as only a limited number of effective antimalarials are available. Drug resistance has been associated with single nucleotide polymorphisms and an increased copy number of multidrug resistance protein 1 (MDR1), an ATP-binding cassette (ABC) protein family member. Many ABC transport proteins are mem- brane transporters that actively translocate a wide range of structurally and functionally diverse amphipathic compounds. The Plasmodium falciparum ABC family consists of 16 members and current knowledge of their physiological function and contribution to antimalarial drug resistance is limited. Here, we give an overview of the Plasmodium ABC family members with reference to their possible role in multidrug resistance. Multidrug resistance in malaria Malaria is one of the major global health problems that was estimated to cause 247 million new cases and nearly one million deaths in 2006 [1], mainly due to Plasmodium falciparum infections in (sub)tropical regions. During the last few decades,many efforts have been made to create a safe and effective vaccine with the objective of malaria eradication; however, the complicated parasite life cycle and unravelled immune response mechanisms have been obstacles, and clinical trials of the most promising vaccine have not resulted in an efficacy above 65% [2,3]. The development of a vaccine will most likely take many more years, and accessibility for people at risk as well as the efficacy of the product will remain a major challenge. In the meantime,conventionaltreatment ofmalaria infec- tions has become increasingly problematic after resistance against easily accessible antimalarials (e.g. chloroquine, sulfadoxine-pyrimethamine and mefloquine) has appeared. Today, only a limited number of effective anti- malarials are available,which has led the World Health Organization to recommend artemisinin based combi- nation therapies to ensure effective treatment and prevent further resistance acquisition. Nonetheless, in vitro susceptibility tests showed resistance to artemisinin derivatives in field isolates [4], and recently a reduced in vivo susceptibility was reported [5]. An important reason for therapeutic failure in malaria treatment could be that drugs do not reach their target sites, due to active extru- sion by the parasite. It has indeed been confirmed that the antimalarial drug chloroquine is extruded from the diges- tive vacuole by the chloroquine resistance transporter (PfCRT) in chloroquine resistant P. falciparum strains [6]. Yet, mutations in PfCRT alone cannot account for the variability in response to chloroquine treatment of differ- ent parasite clones [7]. Most likely other mechanisms contribute to the adapting sensitivity of the parasite to chloroquine. Indeed, the ATP-binding cassette (ABC) transporter family member, multidrug resistance protein 1 (PfMDR1), also named P-glycoprotein homologue (Pgh), has also been associated with chloroquine resistance in vitro [8]. In the last two decades,many studies have concluded that mutations in PfMDR1 and an increased copy number of the PfMDR1 gene are indeed related to resistance against several types of drugs [8,9]. Likewise, single nucleotide polymorphisms in an ABC family member,multidrug resistance-associated protein 1 (PfMRP1), have been linked with reduced drug response in malaria [7]. Recently, the emergenceof reduced artemisinin sensitivity in Cambodia was reported [5].This reduced sensitivity could neither be explained by genetic single nucleotide polymorphisms of PfCRT (not an ABC transporter) and PfMDR1 genes nor by amplification of the PfMDR1 gene.The role of many other ABC transport proteins has not been the subject of investigations. This review summarizes current knowledge ofthe Plasmodium ABC family in relation to multidrug resistance. The ABC transporter family Many ABC transporters actively pump out a wide range of structurally and functionally diverse drugs, thereby decreasing intracellulardrug accumulation, ultimately resulting in drug resistance [10]. The P. falciparum ABC family consists of 16 ABC members [11–13] that have been categorized into subfamilies (A through I)according to phylogenetic analysis of the primary or secondary struc- tures of the conserved nucleotide-binding domains (NBDs) [13–15].The structure of a typical ABC transporter is composed oftwo transmembrane domains (TMDs), each consisting ofsix transmembrane helices (TM),and two cytosolic NBDs.ABC transporters are either encoded as full transporters (TMD-NBD-TMD-NBD) or as half trans- porters (TMD-NBD) that upon translation combine to form a functional unit. The TMDs make up the transmembrane pore that contains one or more substrate-binding sites. ABC transporters, present in the plasma membrane in the Review Corresponding author: Koenderink, J.B.(J.Koenderink@pharmtox.umcn.nl ) 440 1471-4922/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2010.05.002 Trends in Parasitology 26 (2010) 440–446