Transporters involved in resistance to antimalarial drugs

Abstract

The ability to treat and control Plasmodium falciparum infection through chemotherapy has been compromised by the advent and spread of resistance to antimalarial drugs. Research in this area has identified the P. falciparum chloroquine resistance transporter (PfCRT) and the multidrug resistance-1 (PfMDR1) transporter as key determinants of decreased in vitro susceptibility to several principal antimalarial drugs. Transfection-based in vitro studies are consistent with clinical findings of an association between mutations in the pfcrt gene and failure of chloroquine treatment, and between amplification of the pfmdr1 gene and failure of mefloquine treatment. Many countries are now switching to arte-misinin-based combination therapies. These incorporate partner drugs of which some have an in vitro efficacy that can be modulated by changes in pfcrt or pfmdr1. Here, we summarize investigations of these and other recently identified P. falciparum transporters in the context of antimalarial mode of action and mechanisms of resistance. Malaria and drug resistanceThe spread of drug resistant strains of the malaria parasite Plasmodium falciparum has led to a significant resurgence of malarial morbidity and mortality, and a growing crisis in global public health [1]. P. falciparum causes an estimated 500 million clinical infections and at least one million deaths annually, primarily in sub-Saharan Africa [1,2]. Infection begins when Anopheles mosquitoes deliver sporozoite forms that invade hepatocytes and replicate as liverstage parasites, before emerging into the blood stream and infecting red blood cells. The asexual blood-stage infection causes clinical disease characterized by cyclical fevers and shaking chills, which can lead to complications such as severe anemia or cerebral malaria [3,4]. Red blood cells can also harbor sexual-stage gametocytes that can be transmitted to mosquitoes, where they undergo genetic recombination and complete the lifecycle of the parasite.For decades, the treatment of malaria depended on chloroquine -an extensively used 4-aminoquinoline characterized by its rapid efficacy, low toxicity, availability and affordability [5]. The eventual appearance of chloroquine resistance in Southeast Asia and South America sparked the global dissemination of resistance [6]. The first-line treatment for chloroquineresistant (CQR) malaria -sulfadoxine-pyrimethamine -rapidly met with resistance and is also becoming increasingly ineffective [7]. Failure of P. falciparum clinical treatment resulting from confirmed in vivo parasite resistance has now been documented for all current antimalarial drugs apart from the artemisinins, placing artemisinin-based combination therapy at the forefront of current malaria control programs [8,9].Here, we review recent studies into the P. falciparum chloroquine resistance (PfCRT) and multidrug resistance-1 (PfMDR1) transporters that are now known to be key contributors to P. falciparum antimalarial drug resistance. We also briefly discuss the Ca 2+ transporter PfATP6, ...

Polymorphisms of Molecular Markers of Antimalarial Drug Resistance and Relationship with Artesunate-Mefloquine Combination Therapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Thailand

“…Several distinct sequence diversity of point mutations among different geographic areas were detected in individual chloroquine-resistant lines/isolates, particularly the pfcrt K76T, which showed a strong association with chloroquine resistance. 6 For pfmdr1, N86Y mutation was found to be associated with chloroquine resistance in vitro in field isolates or laboratory lines. 7 Amplification of pfmdr1 has also been proposed as a predictor of treatment failure after ACT.…”

Different Patterns of pfcrt and pfmdr1 Polymorphisms in P. falciparum Isolates from Nigeria and Brazil: The Potential Role of Antimalarial Drug Selection Pressure

“…11 Two pfmdr1 mutant alleles/haplotypes occur in CQR strains from different geographic regions; 86Y-184Y-1034S-1042N-1246D predominant in Asia and Africa and 86N-184F-1034C-1042D-1246Y predominant in South America. 11,12 However, a number of field studies have observed a significant non-random association between the CQR pfcrtThr76 and pfmdr1Tyr86 alleles, 13,14 suggesting a joint contribution of these two genes to the CQR phenotype. In this study, we investigated the frequency of pfcrt haplotypes in two different regions of West Africa and South America where chloroquine (CQ) and amodiaquine (AQ), respectively, were widely used.…”

Acinetobacter baylyi ADP1: Transforming the choice of model organism

“…In bacteria, it also contributes to antibiotic resistance, virulence, and vaccine failure (3,4). In eukaryotes, it is associated with cancer and resistance to chemotherapeutics (5,6). Moreover, GDA plays a key role in evolution, particularly in the emergence of new gene functions and in genomic clustering of related genes (7).…”