Mutations in the <named-content content-type="genus-species">Plasmodium falciparum</named-content> Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance

ABSTRACT 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 agains...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/33570c8df3e44fc5aca76e483b8c7bab
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spelling	oai:doaj.org-article:33570c8df3e44fc5aca76e483b8c7bab2021-11-15T15:50:18ZMutations in the <named-content content-type="genus-species">Plasmodium falciparum</named-content> Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance10.1128/mBio.00696-162150-7511https://doaj.org/article/33570c8df3e44fc5aca76e483b8c7bab2016-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00696-16https://doaj.org/toc/2150-7511ABSTRACT 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.Gregory LaMonteMichelle Yi-Xiu LimMelanie WreeChristin ReimerMarie NachonVictoria CoreyPeter GedeckDavid PlouffeAlan DuNelissa FigueroaBryan YeungPablo BifaniElizabeth A. WinzelerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 4 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 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 Mutations in the <named-content content-type="genus-species">Plasmodium falciparum</named-content> Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance
description	ABSTRACT 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.
format	article
author	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
author_facet	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
author_sort	Gregory LaMonte
title	Mutations in the <named-content content-type="genus-species">Plasmodium falciparum</named-content> Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance
title_short	Mutations in the <named-content content-type="genus-species">Plasmodium falciparum</named-content> Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance
title_full	Mutations in the <named-content content-type="genus-species">Plasmodium falciparum</named-content> Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance
title_fullStr	Mutations in the <named-content content-type="genus-species">Plasmodium falciparum</named-content> Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance
title_full_unstemmed	Mutations in the <named-content content-type="genus-species">Plasmodium falciparum</named-content> Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance
title_sort	mutations in the <named-content content-type="genus-species">plasmodium falciparum</named-content> cyclic amine resistance locus (pfcarl) confer multidrug resistance
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/33570c8df3e44fc5aca76e483b8c7bab
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Mutations in the <named-content content-type="genus-species">Plasmodium falciparum</named-content> Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance

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