Novel Pfk13 and Pfubp1 genotypes in African Plasmodium falciparum isolates exhibiting reduced susceptibility to the antimalarials artemisinin and lumefantrine

ABSTRACT Recent evidence indicates that the clinical efficacy of the antimalarial combination artemether-lumefantrine may be compromised by emerging Plasmodium falciparum populations with reduced susceptibility to both components in some parts of East Africa. In vitro s tudies of parasites of Ugandan origin collected in the field and from imported cases in European travelers suggest that partial resistance to the artemisinin component, mediated chiefly by genetic variants in the kelch propeller domain of the pfk13 locus, is arising in concert with increased tolerance of lumefantrine. Genetic determinants of this newly recognized phenotype are unknown. Previous phenotypic and genotypic characterization of six 2022 Ugandan isolates from UK travelers identified two lines, HL2208 and HL2210, with significantly reduced in vitro susceptibility to both artemisinin and lumefantrine and variant alleles of interest at resistance-associated loci. In this study, phenotype-genotype associations are evaluated among an extended panel of 50 P. falciparum isolates collected from UK travelers since 2012. Parasites with reduced ring-stage susceptibility to artemisinin in vitro carrying newly identified or previously established genetic variants in propeller and/or non-propeller domains of pfk13 came from Kenya, Uganda, Zambia, and Namibia. Variant alleles of pfap2μ , pfcoronin, or pfubp1 were also identified in some parasite lines. Among 39 evaluable P. falciparum isolates from 15 different countries tested since 2012, six of the ten least susceptible to lumefantrine were from individuals who had traveled to Uganda. Pfk13- dependent and -independent partial artemisinin resistance has arisen in multiple African settings, providing an opportunity for the development of reduced parasite susceptibility to the partner drug lumefantrine. IMPORTANCE In our studies of UK travelers returning from Africa with malaria, we have encountered a small number of cases where standard combination drugs have failed to completely clear the infection. In this study, we present new assessments of the effectiveness of the major drugs in use against such parasites and link these findings to the genetic profiles of the parasites causing each infection. We identify new genetic types in some of these patient samples that may provide new markers for monitoring malaria drug resistance in African communities.