Title |
Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics
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Published in |
Science, January 2018
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DOI | 10.1126/science.aan4472 |
Pubmed ID | |
Authors |
Annie N. Cowell, Eva S. Istvan, Amanda K. Lukens, Maria G. Gomez-Lorenzo, Manu Vanaerschot, Tomoyo Sakata-Kato, Erika L. Flannery, Pamela Magistrado, Edward Owen, Matthew Abraham, Gregory LaMonte, Heather J. Painter, Roy M. Williams, Virginia Franco, Maria Linares, Ignacio Arriaga, Selina Bopp, Victoria C. Corey, Nina F. Gnädig, Olivia Coburn-Flynn, Christin Reimer, Purva Gupta, James M. Murithi, Pedro A. Moura, Olivia Fuchs, Erika Sasaki, Sang W. Kim, Christine H. Teng, Lawrence T. Wang, Aslı Akidil, Sophie Adjalley, Paul A. Willis, Dionicio Siege, Olga Tanaseichuk, Yang Zhong, Yingyao Zhou, Manuel Llinás, Sabine Ottilie, Francisco-Javier Gamo, Marcus C. S. Lee, Daniel E. Goldberg, David A. Fidock, Dyann F. Wirth, Elizabeth A. Winzeler |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 17 | 21% |
United Kingdom | 10 | 12% |
Canada | 5 | 6% |
Thailand | 2 | 2% |
Venezuela, Bolivarian Republic of | 2 | 2% |
Australia | 2 | 2% |
Ecuador | 2 | 2% |
Spain | 2 | 2% |
Ghana | 2 | 2% |
Other | 7 | 9% |
Unknown | 31 | 38% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 54 | 66% |
Scientists | 25 | 30% |
Practitioners (doctors, other healthcare professionals) | 2 | 2% |
Science communicators (journalists, bloggers, editors) | 1 | 1% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 272 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 64 | 24% |
Researcher | 59 | 22% |
Student > Master | 26 | 10% |
Student > Bachelor | 20 | 7% |
Professor > Associate Professor | 12 | 4% |
Other | 33 | 12% |
Unknown | 58 | 21% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 71 | 26% |
Agricultural and Biological Sciences | 52 | 19% |
Immunology and Microbiology | 20 | 7% |
Chemistry | 15 | 6% |
Medicine and Dentistry | 14 | 5% |
Other | 33 | 12% |
Unknown | 67 | 25% |