CRISPR‐Cas9‐modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine‐containing compounds but potentiates artemisinin‐based combination therapy partner drugs. Issue 3 (7th May 2016)

• Record Type: Journal Article
• Authors: Ng, Caroline L.; Siciliano, Giulia; Lee, Marcus C. S.; de Almeida, Mariana J.; Corey, Victoria C.; Bopp, Selina E.; Bertuccini, Lucia; Wittlin, Sergio; Kasdin, Rachel G.; Le Bihan, Amélie; Clozel, Martine; Winzeler, Elizabeth A.; Alano, Pietro; Fidock, David A.
• Is Part Of: Molecular microbiology. Volume 101:Issue 3(2016)
• Page Start: 381
• Page End: 393
• Publication Date: 2016-05-07
• Subjects: Molecular microbiology -- Periodicals; 572.829
• DOI: 10.1111/mmi.13397
• Languages: English
• ISSNs: 0950-382X

Abstract

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