Search

Your search keyword '"Reimer, C."' showing total 14 results
Start Over Author "Reimer, C." Publisher american society for microbiology
14 results on '"Reimer, C."'

14. Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance.

Author

LaMonte G, Lim MY, Wree M, Reimer C, Nachon M, Corey V, Gedeck P, Plouffe D, Du A, Figueroa N, Yeung B, Bifani P, and Winzeler EA

Subjects
Protozoan Proteins genetics, Recombination, Genetic, Antimalarials pharmacology, Drug Resistance, Multiple, Genetic Loci, Mutation, Plasmodium falciparum drug effects, Plasmodium falciparum genetics
Abstract

Unlabelled: Mutations 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., (Copyright © 2016 LaMonte et al.)

Published
2016
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results