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

• Main Authors: Gregory LaMonte, Michelle Yi-Xiu Lim, Melanie Wree, Christin Reimer, Marie Nachon, Victoria Corey, Peter Gedeck, David Plouffe, Alan Du, Nelissa Figueroa, Bryan Yeung, Pablo Bifani, Elizabeth A. Winzeler
• Format: Article
• Language: English
• Published: American Society for Microbiology 2016-07-01
• Series: mBio
• Online Access: http://mbio.asm.org/cgi/content/full/7/4/e00696-16

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.