CRISPR-Cas9-modifiedpfmdr1protectsPlasmodium falciparumasexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs

摘要: Emerging resistance to first-line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required protect existing drugs enhance efficacy. We report that piperazine-containing compound ACT-451840 exhibits single-digit nanomolar inhibition of Plasmodium falciparum asexual blood stages transmissible gametocyte forms. Genome sequence analyses in vitro-derived ACT-451840-resistant parasites revealed single nucleotide polymorphisms pfmdr1, which encodes a digestive vacuole membrane-bound ATP-binding cassette transporter known alter P. susceptibility multiple antimalarials. CRISPR-Cas9 based gene editing confirmed PfMDR1 point mutations mediated resistance. Resistant demonstrated increased clinical lumefantrine, mefloquine, quinine amodiaquine. Stage V gametocytes harboring Cas9-introduced pfmdr1 also acquired These findings reveal can impart compounds active against mature gametocytes. Exploiting mechanisms provides new opportunities for developing disease-relieving transmission-blocking