Antimalarial drug resistance in Africa: key lessons for the future

Abstract

Drug-resistant parasites repeatedly arise as a result of widespread use of antimalarial drugs and have contributed significantly to the failure to control and eradicate malaria throughout the world. In this review, we describe the spread of resistance to chloroquine and sulfadoxinepyrimethamine, two old drugs that are no longer used owing to high rates of resistance, and examine the effect of the removal of drug pressure on the survival of resistant parasites. Artemisinin-resistant malaria is now emerging in Southeast Asia in a unique and unexpected pattern. We will review the most recent genomic and clinical data to help predict the behavior of resistance to new antimalarial medications and inform strategies to prevent the spread of drugresistant malaria in Africa in the future.

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

“…Most mutant pfcrt alleles come with a fitness cost, indicated in the field by a decrease in their allelic prevalence in the absence of CQ pressure 177 , and in vitro as reduced growth rates when compared to recombinant isogenic parasites expressing the wild-type allele 35,169,178 . Reduced fitness might involve less efficient Hb catabolism and peptide transport in PfCRT mutants, as well as other digestive-vacuole-related physiological processes 178,179 .…”

Antimalarial Drug Resistance: A Threat to Malaria Elimination

“…In addition, in high transmission areas, patients have multiple strain infections transmitted to the mosquito vector. Crossing over of genes during meiosis in the mosquito can then break up resistance and compensatory mutations, and this greater opportunity for recombination will result in increased parasite diversity and direct competition between different parasite strains, with less opportunity for resistant alleles to become fixed (Jiang et al 2011;Takala-Harrison and Laufer 2015). This is not the case in low transmission areas where multiple infections are much less common, infected individuals are less preimmune, usually more prone to be symptomatic, and, as a consequence, to be treated with possible poor-quality antimalarial drugs, incomplete treatment courses, or (artemisinin) monotherapies.…”

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

“…Resistance to treatment regimens, especially the emergence of resistance to artemisinin drugs currently used in combination therapies (2, 3), still poses a threat and highlights the importance of developing treatments containing new chemical classes with different modes of action. The global aim to eradicate malaria brings about additional requirements of chemoprevention and transmission blocking, and the ability to eliminate dormant parasites in the liver that are responsible for relapse in the case of P. vivax infection.…”