Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance

Abstract

Antimalarial drug resistance has historically arisen through convergent <i>de novo</i> mutations in <i>Plasmodium falciparum</i> parasite populations in Southeast Asia and South America. For the past decade in Southeast Asia, artemisinins, the core component of first-line antimalarial therapies, have experienced delayed parasite clearance associated with several <i>pfk13</i> mutations, primarily C580Y. We report that mutant <i>pfk13</i> has emerged independently in Guyana, with genome analysis indicating an evolutionary origin distinct from Southeast Asia. <i>Pfk13</i> C580Y parasites were observed in 1.6% (14/854) of samples collected in Guyana in 2016-2017. Introducing <i>pfk13</i> C580Y or R539T mutations by gene editing into local parasites conferred high levels of <i>in vitro</i> artemisinin resistance. <i>In vitro</i> growth competition assays revealed a fitness cost associated with these <i>pfk13</i> variants, potentially explaining why these resistance alleles have not increased in frequency more quickly in South America. These data place local malaria control efforts at risk in the Guiana Shield.