ArticlemBio2016
Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance.
Article in mBio, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
46 citing papers in PubMed, 69 citations in OpenAlex.
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- Identification of an Orally Efficacious Imidazo[4,5-Journal of medicinal chemistry · 2026Article
- Advancements in CRISPR-Cas Systems for Genome Editing towards Eradication of Human Microbial Pathogens.Molecular biotechnology · 2026Review
- Novel Inhibitors ofJournal of medicinal chemistry · 2025Article
- Towards next-generation treatment options to combat Plasmodium falciparum malaria.Nature reviews. Microbiology · 2025Review
- The essential genome ofScience (New York, N.Y.) · 2025Article
- Systematic in vitro evolution inScience (New York, N.Y.) · 2024Article
- In vitro evaluation of ganaplacide/lumefantrine combination against Plasmodium falciparum in a context of artemisinin resistance.The Journal of antimicrobial chemotherapy · 2024Article
- A kalihinol analog disrupts apicoplast function and vesicular trafficking inScience (New York, N.Y.) · 2024Article
- Plasmodium SEY1 is a novel druggable target that contributes to imidazolopiperazine mechanism of action.Research square · 2024Article
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- Understanding the Antiplasmodial Action of Resistance-Refractory Xanthoquinodin A1.ACS infectious diseases · 2024Article
- Antifungal profile against Candida auris clinical isolates of tyroscherin and its new analog produced by the deep-sea-derived fungal strain Scedosporium apiospermum FKJ-0499.The Journal of antibiotics · 2024Article
- Antiplasmodial peptaibols act through membrane directed mechanisms.Cell chemical biology · 2024Article
- Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases.Journal of medicinal chemistry · 2024Article
- Single-cell quantitative bioimaging ofmSphere · 2023Article
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- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
unlabelledMutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) are associated with parasite resistance to the imidazolopiperazines, a potent class of novel antimalarial compounds that display both prophylactic and transmission-blocking activity, in addition to activity against blood-stage parasites. Here, we show that pfcarl encodes a protein, with a predicted molecular weight of 153 kDa, that localizes to the cis-Golgi apparatus of the parasite in both asexual and sexual blood stages. Utilizing clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene introduction of 5 variants (L830V, S1076N/I, V1103L, and I1139K), we demonstrate that mutations in pfcarl are sufficient to generate resistance against the imidazolopiperazines in both asexual and sexual blood-stage parasites. We further determined that the mutant PfCARL protein confers resistance to several structurally unrelated compounds. These data suggest that PfCARL modulates the levels of small-molecule inhibitors that affect Golgi-related processes, such as protein sorting or membrane trafficking, and is therefore an important mechanism of resistance in malaria parasites. IMPORTANCE: Several previous in vitro evolution studies have implicated the Plasmodium falciparum cyclic amine resistance locus (PfCARL) as a potential target of imidazolopiperazines, potent antimalarial compounds with broad activity against different parasite life cycle stages. Given that the imidazolopiperazines are currently being tested in clinical trials, understanding their mechanism of resistance and the cellular processes involved will allow more effective clinical usage.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.