Dataset Information

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics.

ABSTRACT: Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target-inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.

SUBMITTER: Cowell AN

PROVIDER: S-EPMC5925756 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics.

Cowell Annie N AN Istvan Eva S ES Lukens Amanda K AK Gomez-Lorenzo Maria G MG Vanaerschot Manu M Sakata-Kato Tomoyo T Flannery Erika L EL Magistrado Pamela P Owen Edward E Abraham Matthew M LaMonte Gregory G Painter Heather J HJ Williams Roy M RM Franco Virginia V Linares Maria M Arriaga Ignacio I Bopp Selina S Corey Victoria C VC Gnädig Nina F NF Coburn-Flynn Olivia O Reimer Christin C Gupta Purva P Murithi James M JM Moura Pedro A PA Fuchs Olivia O Sasaki Erika E Kim Sang W SW Teng Christine H CH Wang Lawrence T LT Akidil Aslı A Adjalley Sophie S Willis Paul A PA Siegel Dionicio D Tanaseichuk Olga O Zhong Yang Y Zhou Yingyao Y Llinás Manuel M Ottilie Sabine S Gamo Francisco-Javier FJ Lee Marcus C S MCS Goldberg Daniel E DE Fidock David A DA Wirth Dyann F DF Winzeler Elizabeth A EA

Science (New York, N.Y.) 20180101 6372

Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 <i>Plasmodium falciparum</i> parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previo ...[more]

PMID: 29326268

Similar Datasets

Project description:Malaria parasites are unicellular organisms residing inside the red blood cells, and current methods for editing the parasite genes have been inefficient. The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats and Cas9 endonuclease-mediated genome editing) system is a new powerful technique for genome editing and has been widely employed to study gene function in various organisms. However, whether this technique can be applied to modify the genomes of malaria parasites has not been determined. In this paper, we demonstrated that Cas9 is able to introduce site-specific DNA double-strand breaks in the Plasmodium yoelii genome that can be repaired through homologous recombination. By supplying engineered homologous repair templates, we generated targeted deletion, reporter knock-in, and nucleotide replacement in multiple parasite genes, achieving up to 100% efficiency in gene deletion and 22 to 45% efficiencies in knock-in and allelic replacement. Our results establish methodologies for introducing desired modifications in the P. yoelii genome with high efficiency and accuracy, which will greatly improve our ability to study gene function of malaria parasites. Importance: Malaria, caused by infection of Plasmodium parasites, remains a world-wide public health burden. Although the genomes of many malaria parasites have been sequenced, we still do not know the functions of approximately half of the genes in the genomes. Studying gene function has become the focus of many studies; however, editing genes in malaria parasite genomes is still inefficient. Here we designed several efficient approaches, based on the CRISPR/Cas9 system, to introduce site-specific DNA double-strand breaks in the Plasmodium yoelii genome that can be repaired through homologous recombination. Using this system, we achieved high efficiencies in gene deletion, reporter tagging, and allelic replacement in multiple parasite genes. This technique for editing the malaria parasite genome will greatly facilitate our ability to elucidate gene function.

Dataset Information

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics.

Publications

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets