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

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 La Monte; 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; Asl Akidil; Sophie Adjalley; Paul A. Willis; Dionicio Siegel; 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

doi:10.1126/science.aan4472

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

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 La Monte, Heather J. Painter, Roy M. Williams, Virginia Franco, Maria Linares, Ignacio Arriaga, Selina Bopp, Victoria C. Corey, Nina F. Gnädig, Olivia Coburn-FlynnChristin Reimer, Purva Gupta, James M. Murithi, Pedro A. Moura, Olivia Fuchs, Erika Sasaki, Sang W. Kim, Christine H. Teng, Lawrence T. Wang, Asl Akidil, Sophie Adjalley, Paul A. Willis, Dionicio Siegel, 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

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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, farnesytransferase 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.

Original language	English (US)
Pages (from-to)	191-199
Number of pages	9
Journal	Science
Volume	359
Issue number	6372
DOIs	https://doi.org/10.1126/science.aan4472
State	Published - Jan 12 2018

All Science Journal Classification (ASJC) codes

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10.1126/science.aan4472

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Cowell, A. N., Istvan, E. S., Lukens, A. K., Gomez-Lorenzo, M. G., Vanaerschot, M., Sakata-Kato, T., Flannery, E. L., Magistrado, P., Owen, E., Abraham, M., La Monte, G., Painter, H. J., Williams, R. M., Franco, V., Linares, M., Arriaga, I., Bopp, S., Corey, V. C., Gnädig, N. F., ... Winzeler, E. A. (2018). Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science, 359(6372), 191-199. https://doi.org/10.1126/science.aan4472

@article{18ab0d42ab524a4aaf7222b794c8efab,

title = "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, farnesytransferase 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.",

author = "Cowell, {Annie N.} and Istvan, {Eva S.} and Lukens, {Amanda K.} and Gomez-Lorenzo, {Maria G.} and Manu Vanaerschot and Tomoyo Sakata-Kato and Flannery, {Erika L.} and Pamela Magistrado and Edward Owen and Matthew Abraham and {La Monte}, Gregory and Painter, {Heather J.} and Williams, {Roy M.} and Virginia Franco and Maria Linares and Ignacio Arriaga and Selina Bopp and Corey, {Victoria C.} and Gn{\"a}dig, {Nina F.} and Olivia Coburn-Flynn and Christin Reimer and Purva Gupta and Murithi, {James M.} and Moura, {Pedro A.} and Olivia Fuchs and Erika Sasaki and Kim, {Sang W.} and Teng, {Christine H.} and Wang, {Lawrence T.} and Asl Akidil and Sophie Adjalley and Willis, {Paul A.} and Dionicio Siegel and Olga Tanaseichuk and Yang Zhong and Yingyao Zhou and Manuel Llin{\'a}s and Sabine Ottilie and Gamo, {Francisco Javier} and Lee, {Marcus C.S.} and Goldberg, {Daniel E.} and Fidock, {David A.} and Wirth, {Dyann F.} and Winzeler, {Elizabeth A.}",

note = "Funding Information: This work was supported by grants from the Bill and Melinda Gates Foundation (OPP1040406 and OPP1119049), the National Institutes of Health (P50GM085764), and the National Institute of Allergy and Infectious Diseases (NIAID; R01AI103058 and R01AI50234). Whole-genome sequencing was performed at the Institute for Genomic Medicine Genomic Center, UCSD. We thank the Penn State Metabolomics Core Facility (University Park, PA) for critical analytical expertise. A.C. received support from the UCSD Division of Infectious Diseases institutional NIAID training grant (T32AI007036). E.L.F. received support from a NIAID National Research Service Award fellowship (F32AI102567). V.C. received support from a UCSD Genetics Training Program through an institutional training grant from the National Institute of General Medical Sciences (T32GM008666). G.M.L. is supported by an A.P. Giannini Post-Doctoral Fellowship. The authors declare no competing financial interests. The red blood cells used in this work were sourced ethically, and their research use was in accord with the terms of the informed consents. All relevant sequence data that were not previously published have been deposited in the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) database with accession code SRP096299. Previously published sequences are deposited in the NCBI SRA with the accession codes listed in table S3. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. This license does not apply to figures/ photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.",

year = "2018",

month = jan,

day = "12",

doi = "10.1126/science.aan4472",

language = "English (US)",

volume = "359",

pages = "191--199",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6372",

}

Cowell, AN, Istvan, ES, Lukens, AK, Gomez-Lorenzo, MG, Vanaerschot, M, Sakata-Kato, T, Flannery, EL, Magistrado, P, Owen, E, Abraham, M, La Monte, G, Painter, HJ, Williams, RM, Franco, V, Linares, M, Arriaga, I, Bopp, S, Corey, VC, Gnädig, NF, Coburn-Flynn, O, Reimer, C, Gupta, P, Murithi, JM, Moura, PA, Fuchs, O, Sasaki, E, Kim, SW, Teng, CH, Wang, LT, Akidil, A, Adjalley, S, Willis, PA, Siegel, D, Tanaseichuk, O, Zhong, Y, Zhou, Y, Llinás, M, Ottilie, S, Gamo, FJ, Lee, MCS, Goldberg, DE, Fidock, DA, Wirth, DF & Winzeler, EA 2018, 'Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics', Science, vol. 359, no. 6372, pp. 191-199. https://doi.org/10.1126/science.aan4472

TY - JOUR

T1 - Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics

AU - Cowell, Annie N.

AU - Istvan, Eva S.

AU - Lukens, Amanda K.

AU - Gomez-Lorenzo, Maria G.

AU - Vanaerschot, Manu

AU - Sakata-Kato, Tomoyo

AU - Flannery, Erika L.

AU - Magistrado, Pamela

AU - Owen, Edward

AU - Abraham, Matthew

AU - La Monte, Gregory

AU - Painter, Heather J.

AU - Williams, Roy M.

AU - Franco, Virginia

AU - Linares, Maria

AU - Arriaga, Ignacio

AU - Bopp, Selina

AU - Corey, Victoria C.

AU - Gnädig, Nina F.

AU - Coburn-Flynn, Olivia

AU - Reimer, Christin

AU - Gupta, Purva

AU - Murithi, James M.

AU - Moura, Pedro A.

AU - Fuchs, Olivia

AU - Sasaki, Erika

AU - Kim, Sang W.

AU - Teng, Christine H.

AU - Wang, Lawrence T.

AU - Akidil, Asl

AU - Adjalley, Sophie

AU - Willis, Paul A.

AU - Siegel, Dionicio

AU - Tanaseichuk, Olga

AU - Zhong, Yang

AU - Zhou, Yingyao

AU - Llinás, Manuel

AU - Ottilie, Sabine

AU - Gamo, Francisco Javier

AU - Lee, Marcus C.S.

AU - Goldberg, Daniel E.

AU - Fidock, David A.

AU - Wirth, Dyann F.

AU - Winzeler, Elizabeth A.

N1 - Funding Information: This work was supported by grants from the Bill and Melinda Gates Foundation (OPP1040406 and OPP1119049), the National Institutes of Health (P50GM085764), and the National Institute of Allergy and Infectious Diseases (NIAID; R01AI103058 and R01AI50234). Whole-genome sequencing was performed at the Institute for Genomic Medicine Genomic Center, UCSD. We thank the Penn State Metabolomics Core Facility (University Park, PA) for critical analytical expertise. A.C. received support from the UCSD Division of Infectious Diseases institutional NIAID training grant (T32AI007036). E.L.F. received support from a NIAID National Research Service Award fellowship (F32AI102567). V.C. received support from a UCSD Genetics Training Program through an institutional training grant from the National Institute of General Medical Sciences (T32GM008666). G.M.L. is supported by an A.P. Giannini Post-Doctoral Fellowship. The authors declare no competing financial interests. The red blood cells used in this work were sourced ethically, and their research use was in accord with the terms of the informed consents. All relevant sequence data that were not previously published have been deposited in the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) database with accession code SRP096299. Previously published sequences are deposited in the NCBI SRA with the accession codes listed in table S3. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. This license does not apply to figures/ photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.

PY - 2018/1/12

Y1 - 2018/1/12

N2 - 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, farnesytransferase 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.

AB - 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, farnesytransferase 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.

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U2 - 10.1126/science.aan4472

DO - 10.1126/science.aan4472

M3 - Article

C2 - 29326268

AN - SCOPUS:85040443759

SN - 0036-8075

VL - 359

SP - 191

EP - 199

JO - Science

JF - Science

IS - 6372

ER -

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

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