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Mutations in the P. falciparum Cyclic Amine Resistance Locus (PfCARL) confer multi-drug resistance

LaMonte, Gregory , Lim, Michelle, Wree, Melanie , Nachon, Marie , Corey, Victoria , Plouffe, David, Gedeck, Peter, Du, Alan , Figueroa, Nelissa , Yeung, Bryan King Sing, Bifani, Juan Pablo and Winzeler, Elizabeth (2016) Mutations in the P. falciparum Cyclic Amine Resistance Locus (PfCARL) confer multi-drug resistance. mBio, 7 (4). 00696-00716. ISSN 2161-2129; 2150-7511

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The Plasmodium falciparum cyclic amine resistance locus (pfcarl) has been associated with parasite resistance to the imidazolopiperazines, a potent class of novel antimalarial compounds that displays prophylactic and transmission-blocking activity in addition to activity against blood-stage parasites. Here, we show that pfcarl encodes a protein with an expected molecular weight of 153kd that localizes to the cis-Golgi of the parasite in both asexual and sexual blood stages. Utilizing Crispr-mediated gene introduction of 5 variants (L830V, S1076N/I, V1103L and I1139K), we demonstrate that pfcarl mutations are sufficient to generate resistance against the imidazolopiperazines in asexual and sexual stage parasites. We further find that pfcarl confers resistance to a number of 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. Pfcarl is therefore an important mechanism of resistance in malaria parasites.

Item Type: Article
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45