Institute of Tropical Medicine Antwerp
Foundation of Public Utility

Identification of antimalarial compounds that require CLAG3 for their uptake by P. falciparum-infected erythrocytes

DSpace/Manakin Repository

Show simple item record Mira-Martinez, S. en_US Pickford, A. K. en_US Rovira-Graells, N. en_US Guetens, P. en_US Tinto-Font, E. en_US Cortes, A. en_US Rosanas-Urgell, A. en_US 2019-06-04T12:20:41Z 2019-06-04T12:20:41Z 2019 en_US
dc.identifier.issn 0066-4804 en_US
dc.identifier.doi en_US
dc.identifier.other 14 pp. en_US
dc.identifier.other 56 en_US
dc.identifier.other ITG-B1B; ITG-BLA; DBM; U-MALAR; JIF; DOI; PDF; Abstract; ITMPUB; DSPACE66 en_US
dc.description.abstract During the intraerythrocytic asexual cycle malaria parasites acquire nutrients and other solutes through a broad selectivity channel localized at the membrane of the infected erythrocyte termed Plasmodial Surface Anion Channel (PSAC). The protein product of the Plasmodium falciparum clonally variant clag3.1 and clag3.2 genes determines PSAC activity. Switches in the expression of clag3 genes, which are regulated by epigenetic mechanisms, are associated with changes in PSAC-dependent permeability that can result in resistance to compounds toxic for the parasite such as blasticidin S. Here we investigated whether other antimalarial drugs require CLAG3 to reach their intracellular target and consequently are prone to parasite resistance by epigenetic mechanisms. We found that the bis-thiazolium salts T3 (also known as albitiazolium) and T16 require the product of clag3 genes to enter infected erythrocytes. P. falciparum populations can develop resistance to these compounds via selection of parasites with dramatically reduced expression of both genes. However, other compounds previously demonstrated or predicted to enter infected erythrocytes through transport pathways absent from non-infected erythrocytes, such as fosmidomycin, doxycycline, azithromycin, lumefantrine or pentamidine, do not require expression of clag3 genes for their anti-malarial activity. This suggests that they use alternative CLAG3-independent routes to access parasites. Our results demonstrate that P. falciparum can develop resistance to diverse antimalarial compounds by epigenetic changes in the expression of clag3 genes. This is of concern for drug development efforts because drug resistance by epigenetic mechanisms can arise quickly, even during the course of a single infection. en_US
dc.language English en_US
dc.relation.uri en_US
dc.subject Malaria en_US
dc.subject Protozoal diseases en_US
dc.subject Treatment en_US
dc.subject Antimalarials en_US
dc.subject Plasmodium falciparum en_US
dc.title Identification of antimalarial compounds that require CLAG3 for their uptake by P. falciparum-infected erythrocytes en_US
dc.type Article-E en_US
dc.citation.issue 5 en_US
dc.citation.jtitle Antimicrobial Agents and Chemotherapy en_US
dc.citation.volume 63 en_US
dc.citation.abbreviation Antimicrob Agents Chemother en_US

Files in this item

This item appears in the following Collection(s)

Show simple item record