The evolution of drug-resistant malaria

Abstract

Molecular epidemiological investigations have uncovered the patterns of emergence and global spread of Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine. Malaria parasites highly resistant to chloroquine and pyrimethamine spread from Asian origins to Africa, at great cost to human health and life. If artemisinin-resistant falciparum malaria follows the same pattern, renewed efforts to eliminate and eradicate malaria will be gravely threatened. This paper, adapted from a talk given in honour of Professor Malcolm Molyneux in Liverpool in September 2008, reviews the rise and fall of clinically important forms of drug-resistant falciparum malaria and considers how lessons learned from studying the evolution of drug-resistant malaria can be applied to efforts to prevent and deter resistance.

Figure 1

Schematic representation of the patterns of origin and dissemination of low-grade resistance of Plasmodium falciparum to pyrimethamine caused by a single dihydrofolate reductase (DHFR) mutation that arose independently many times in response to local drug pressure (left); clinically significant pyrimethamine resistance caused by the ‘triple mutant’ DHFR, which may have arisen only twice, spreading from Asia to Africa (centre); and chloroquine resistance caused by the pfcrt K76T mutation on a variable background of other pfcrt mutations, which has arisen a handful of times, with the major Asian and African forms sharing a common Southeast Asian origin (right). Patterns of origin and spread are inferred from the chronology of historical reports of resistance and later molecular epidemiological analyses of the drug resistance-encoding genes and surrounding microsatellites and other genetic markers as described in references , and and other sources. Arrows represent approximate patterns of spread from original foci and are not an accurate representation of the current distribution of resistant parasites of different ancestral origins.