The interplay between drug resistance and fitness in malaria parasites

Abstract

SummaryControlling the spread of antimalarial drug resistance, especially resistance of Plasmodium falciparum to artemisinin-based combination therapies, is a high priority. Available data indicate that, as with other microorganisms, the spread of drug-resistant malaria parasites is limited by fitness costs that frequently accompany resistance. Resistance-mediating polymorphisms in malaria parasites have been identified in putative drug transporters and in target enzymes. The impacts of these polymorphisms on parasite fitness have been characterized in vitro and in animal models. Additional insights have come from analyses of samples from clinical studies, both evaluating parasites under different selective pressures and determining the clinical consequences of infection with different parasites. With some exceptions, resistance-mediating polymorphisms lead to malaria parasites that, compared to wild type, grow less well in culture and in animals, and are replaced by wild type when drug pressure diminishes in the clinical setting. In some cases, the fitness costs of resistance may be offset by compensatory mutations that increase virulence or changes that enhance malaria transmission. However, not enough is known about effects of resistance mediators on parasite fitness. A better appreciation of the costs of fitness-mediating mutations will facilitate the development of optimal guidelines for the treatment and prevention of malaria.

Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1

“…Despite recent progress in some regions, the treatment and control of the disease are challenged by increasing resistance to available therapies (2). New drugs to treat malaria are needed.…”

“…Rather, they showed an SNP and increased copy number in pfmdr1, which encodes a putative transporter on the surface of the P. falciparum food vacuole, in which plasmepsins I to IV contribute to the essential process of hemoglobin hydrolysis (4). Alterations in pfmdr1, including both SNPs and increased copy number, are associated with altered sensitivity to a number of antimalarials (2). SNPs were also seen in resistant parasites in two other genes.…”

Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

“…Resistance to the aminoquinolines chloroquine and amodiaquine is mediated largely by polymorphisms in putative drug transporters encoded by pfcrt and pfmdr1 (13,17), and these polymorphisms are selected in new infections that emerge soon after Citation Nankabirwa JI, Conrad MD, Legac J, Tukwasibwe S, Tumwebaze P, Wandera B, Brooker SJ, Staedke SG, Kamya MR, Nsobya SL, Dorsey G, Rosenthal PJ. 2016.…”

“…IPT is standard practice during pregnancy (IPTp), is recommended for children living in seasonal malaria transmission settings as seasonal malaria chemoprevention (5), and is being investigated in other populations (6)(7)(8)(9). However, currently IPT is advocated only with sulfadoxine-pyrimethamine (SP) or a combination of SP and amodiaquine (SP-AQ) (5,10), regimens that are severely compromised by drug resistance in much of Africa (11)(12)(13). For malaria treatment, older regimens have been replaced by artemisinin-based combination therapies (ACTs), and a similar change may be warranted for IPT.…”

“…Resistance to the aminoquinolines chloroquine and amodiaquine is mediated largely by polymorphisms in putative drug transporters encoded by pfcrt and pfmdr1 (13,17), and these polymorphisms are selected in new infections that emerge soon after therapy with artesunate-AQ (AS-AQ) (18,19). Piperaquine is a bisaminoquinoline related to chloroquine and amodiaquine.…”