Acta Tropica 94 (2005) 181–190 Contribution of the pfmdr1 gene to antimalarial drug-resistance Manoj T. Duraisingh a , Alan F. Cowman b,* a Harvard School of Public Health, 665 Huntington Avenue, Boston, MA, USA b Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Vic. 3050, Australia Abstract The emergence of drug-resistance poses a major obstacle to the control of malaria. A homolog of the major multidrug- transporter in mammalian cells was identified, Plasmodium falciparum multidrug resistance protein-1, pfmdr1, also known as the P-glycoprotein homolog 1, Pgh-1. Several studies have demonstrated strong, although incomplete, associations between resistance to the widely used antimalarial drug chloroquine and mutation of the pfmdr1 gene in both laboratory and field isolates. Genetic studies have confirmed a link between mutation of the pfmdr1 gene and chloroquine-resistance. Although not essential for chloroquine-resistance, pfmdr1 plays a role in modulating levels of resistance. At the same time it appears to be a significant component in resistance to the structurally related drug quinine. A strong association has been observed between possession of the wildtype form of pfmdr1, amplification of pfmdr1 and resistance to hydrophobic drugs such as the arylaminoalcohol mefloquine and the endoperoxide artemisinin derivatives in field isolates. This is supported by genetic studies. The arylaminoalcohol and endoperoxide drugs are structurally unrelated drugs and this resistance resembles true multidrug resistance. Polymorphism in pfmdr1 and gene amplification has been observed throughout the world and their usefulness in predicting resistance levels is influenced by the history of drug selection of each population. © 2005 Elsevier B.V. All rights reserved. Keywords: Drug-resistance; Chloroquine; Plasmodium falciparum 1. Problem of drug-resistance: chloroquine-resistance and multi-drug resistance Antimalarial drug-resistance poses one of the great- est threats to the control of malaria. The cheap and widely available first-line drug chloroquine has become largely ineffective where malaria is present due to the emergence and spread of chloroquine-resistance. * Corresponding author. Tel.: +61 3 9345 2446. E-mail address: cowman@wehi.edu.au (A.F. Cowman). Arylaminoalcohol drugs such as mefloquine and halofantrine have been introduced as second-line drugs in areas of high level chloroquine-resistance. Resis- tance to these drugs has also emerged and in certain areas such as the border areas of Thailand, it has in- creased to a point where their use in monotherapy has been compromised (Price et al., 1995). The recently introduced endoperoxide drugs are highly efficacious against parasite lines resistant to the other antimalarials. Nevertheless a reduction in in vitro sensitivity is observed in areas of mefloquine- resistance (Chou et al., 1980; Price et al., 1999a), 0001-706X/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.actatropica.2005.04.008