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

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)381-393
Number of pages13
JournalMolecular Microbiology
Volume101
Issue number3
DOIs
StatePublished - Aug 1 2016

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Clustered Regularly Interspaced Short Palindromic Repeats
Antimalarials
Plasmodium falciparum
Combination Drug Therapy
Parasites
Amodiaquine
Mefloquine
Mutation
ATP-Binding Cassette Transporters
Quinine
Vacuoles
Point Mutation
Pharmaceutical Preparations
Malaria
Single Nucleotide Polymorphism
Sequence Analysis
Therapeutics
Genome
Membranes
artemisinine

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

Cite this

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. / 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.

In: Molecular Microbiology, Vol. 101, No. 3, 01.08.2016, p. 381-393.

Research output: Contribution to journalArticle

Ng, CL, Siciliano, G, Lee, MCS, de Almeida, MJ, Corey, VC, Bopp, SE, Bertuccini, L, Wittlin, S, Kasdin, RG, Le Bihan, A, Clozel, M, Winzeler, EA, Alano, P & Fidock, DA 2016, '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', Molecular Microbiology, vol. 101, no. 3, pp. 381-393. https://doi.org/10.1111/mmi.13397
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. / 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. In: Molecular Microbiology. 2016 ; Vol. 101, No. 3. pp. 381-393.
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