P. falciparum K13 mutations present varying degrees of artemisinin resistance and reduced fitness in African parasites

Stokes, Barbara H.; Rubiano, Kelly; Dhingra, Satish K.; Mok, Sachel; Straimer, Judith; Gnädig, Nina F.; Bath, Jade R.; Deni, Ioanna; Ward, Kurt E.; Striepen, Josefine; Yeo, Tomas; Ross, Leila S.; Legrand, Eric; Ariey, Frédéric; Cunningham, Clark H.; Souleymane, Issa M.; Gansané, Adama; Nzoumbou-Boko, Romaric; Ndayikunda, Claudette; Kabanywanyi, Abdunoor M.; Uwimana, Aline; Smith, Samuel J.; Kolley, Olimatou; Ndounga, Mathieu; Warsame, Marian; Leang, Rithea; Nosten, François; Anderson, Timothy J.C.; Rosenthal, Philip J.; Ménard, Didier; Fidock, David A.

The emergence of artemisinin (ART) resistance in Plasmodium falciparum parasites, driven by K13 mutations, has led to widespread antimalarial treatment failure in Southeast Asia. In Africa, our genotyping of 3,299 isolates confirms the emergence of the K13 R561H variant in Rwanda and reveals the continuing dominance of wild-type K13 across 11 countries. We show that this mutation, along with M579I and C580Y, confers varying degrees of in vitro ART resistance in African parasites. C580Y and M579I cause substantial fitness costs, which may counter-select against their dissemination in high-transmission settings. We also define the impact of multiple K13 mutations on ART resistance and fitness in multiple Southeast Asian strains. ART susceptibility is unaltered upon editing point mutations in ferrodoxin or mdr2, earlier resistance markers. These data point to the lack of an evident biological barrier to mutant K13 mediating ART resistance in Africa, while identifying their detrimental impact on parasite growth.