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 |
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| Authors: | Caroline L Ng Giulia Siciliano Marcus C S Lee Mariana J de Almeida Victoria C Corey Selina E Bopp Lucia Bertuccini Sergio Wittlin Rachel G Kasdin Amélie Le Bihan Martine Clozel Elizabeth A Winzeler Pietro Alano David A Fidock |
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| Institution: | 1. Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA;2. Dipartimento di Malattie Infettive, Parassitarie ed Immunomediate, Istituto Superiore di Sanità, 00161 Rome, Italy;3. Division of Host‐Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA, USA;4. Dipartimento Tecnologie e Salute, Istituto Superiore di Sanità, 00161 Rome, Italy;5. Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland;6. Department of Drug Discovery, Actelion Pharmaceuticals Ltd., CH-4123 Allschwil, Switzerland;7. Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA |
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| Abstract: | 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. |
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