A novel locus associated with decreased susceptibility of Plasmodium falciparum to lumefantrine and dihydroartemisinin has emerged and spread in Uganda

Malaria control in Uganda is threatened by the emergence of artemisinin partial resistance (ART-R) and decreasing lumefantrine susceptibility. To identify loci contributing to decreased drug susceptibility, we assessed signatures of selection in Ugandan whole genome Plasmodium falciparum sequences. Extended shared haplotypes were seen for the ART-R associated Kelch13 (K13) C469Y and A675V mutations, but the strongest signal of recent selection was centered on a segment of chromosome 7 encoding the phosphoinositide-binding protein gene (px1, PF3D7_0720700). A haplotype, represented by three PX1 SNPs (L1222P, M1701I and D1705N) and two indels (designated PIN), was first seen in 2008 and rapidly increased, reaching prevalence >50% in northern Uganda by 2016 and eastern Uganda by 2023. PIN-carrying parasites showed significantly decreased ex vivo susceptibilities, measured as IC50s, to lumefantrine, mefloquine and dihydroartemisinin, either with or without coincident K13 mutations. Thus, PX1 polymorphisms may impact on the susceptibilities of African malaria parasites to key drugs.