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

LaMonte, Gregory and Lim, Michelle and Wree, Melanie and Nachon, Marie and Corey, Victoria and Plouffe, David and Gedeck, Peter and Du, Alan and Figueroa, Nelissa and Yeung, Bryan King Sing and 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

Official URL: http://www.asm.org/

Abstract

Abstract
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
URI: https://oak.novartis.com/id/eprint/28286

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