Genomewide Scan Reveals Amplification of mdr1 as a Common Denominator of Resistance to Mefloquine, Lumefantrine, and Artemisinin in Plasmodium chabaudi Malaria Parasites

被引：30

作者：

Borges, Sofia ^{[1
]}

Cravo, Pedro ^{[4
]}

Creasey, Alison ^{[2
]}

Fawcett, Richard ^{[2
]}

Modrzynska, Katarzyna ^{[2
]}

Rodrigues, Louise ^{[1
]}

Martinelli, Axel ^{[1
]}

Hunt, Paul ^{[2
,3
]}

机构：

[1] Univ Nova Lisboa, UEI Malaria, Ctr Malaria & Outras Doencas Trop, Inst Higiene & Med Trop,UEI Biol Mol, P-1349008 Lisbon, Portugal

[2] Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Edinburgh EH9 3JT, Midlothian, Scotland

[3] Univ Edinburgh, Sch Biol Sci, Ctr Immun Infect & Evolut, Edinburgh EH9 3JT, Midlothian, Scotland

[4] Univ Fed Goias, Inst Patol Trop & Saude Publ, BR-74605050 Goiania, Go, Brazil

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2011年 / 55卷 / 10期

基金：

英国医学研究理事会;

关键词：

PFMDR1 COPY NUMBER; HALOFANTRINE RESISTANCE; FALCIPARUM-MALARIA; GENE; SELECTION; DETERMINANTS; MUTATION; LINKAGE; ENZYME; BORDER;

D O I：

10.1128/AAC.01748-10

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Multidrug-resistant Plasmodium falciparum malaria parasites pose a threat to effective drug control, even to artemisinin-based combination therapies (ACTs). Here we used linkage group selection and Solexa whole-genome resequencing to investigate the genetic basis of resistance to component drugs of ACTs. Using the rodent malaria parasite P. chabaudi, we analyzed the uncloned progeny of a genetic backcross between the mefloquine-, lumefantrine-, and artemisinin-resistant mutant AS-15MF and a genetically distinct sensitive clone, AJ, following drug treatment. Genomewide scans of selection showed that parasites surviving each drug treatment bore a duplication of a segment of chromosome 12 (translocated to chromosome 04) present in AS-15MF. Whole-genome resequencing identified the size of the duplicated segment and its position on chromosome 4. The duplicated fragment extends for similar to 393 kbp and contains over 100 genes, including mdr1, encoding the multidrug resistance P-glycoprotein homologue 1. We therefore show that resistance to chemically distinct components of ACTs is mediated by the same genetic mutation, highlighting a possible limitation of these therapies.

引用

页码：4858 / 4865

页数：8

共 37 条

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