Abstract：
BACKGROUND:Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. RESULTS:We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. CONCLUSIONS:We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use.
journal_name
Genome Bioljournal_title
Genome biologyauthors
Herman JD,Rice DP,Ribacke U,Silterra J,Deik AA,Moss EL,Broadbent KM,Neafsey DE,Desai MM,Clish CB,Mazitschek R,Wirth DFdoi
10.1186/PREACCEPT-1067113631444973subject
Has Abstractpub_date
2014-01-01 00:00:00pages
511issue
11eissn
1474-7596issn
1474-760Xpii
s13059-014-0511-2journal_volume
15pub_type
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