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

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)191-199
Number of pages9
JournalScience
Volume359
Issue number6372
DOIs
StatePublished - Jan 12 2018

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Malaria
Parasites
Gene Amplification
Genome
Plasmodium falciparum
Drug Resistance
Thymidylate Synthase
Antimalarials
Multiple Drug Resistance
Drug Discovery
Genes
Pharmaceutical Preparations
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • General

Cite this

Cowell, A. N., Istvan, E. S., Lukens, A. K., Gomez-Lorenzo, M. G., Vanaerschot, M., Sakata-Kato, T., ... 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
Cowell, Annie N. ; Istvan, Eva S. ; Lukens, Amanda K. ; Gomez-Lorenzo, Maria G. ; Vanaerschot, Manu ; Sakata-Kato, Tomoyo ; Flannery, Erika L. ; Magistrado, Pamela ; Owen, Edward ; Abraham, Matthew ; La Monte, Gregory ; Painter, Heather J. ; Williams, Roy M. ; Franco, Virginia ; Linares, Maria ; Arriaga, Ignacio ; Bopp, Selina ; Corey, Victoria C. ; Gnädig, Nina F. ; Coburn-Flynn, Olivia ; Reimer, Christin ; Gupta, Purva ; Murithi, James M. ; Moura, Pedro A. ; Fuchs, Olivia ; Sasaki, Erika ; Kim, Sang W. ; Teng, Christine H. ; Wang, Lawrence T. ; Akidil, Asl ; Adjalley, Sophie ; Willis, Paul A. ; Siegel, Dionicio ; Tanaseichuk, Olga ; Zhong, Yang ; Zhou, Yingyao ; Llinás, Manuel ; Ottilie, Sabine ; Gamo, Francisco Javier ; Lee, Marcus C.S. ; Goldberg, Daniel E. ; Fidock, David A. ; Wirth, Dyann F. ; Winzeler, Elizabeth A. / Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. In: Science. 2018 ; Vol. 359, No. 6372. pp. 191-199.
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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.",
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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

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. / Cowell, Annie N.; Istvan, Eva S.; Lukens, Amanda K.; Gomez-Lorenzo, Maria G.; Vanaerschot, Manu; Sakata-Kato, Tomoyo; Flannery, Erika L.; Magistrado, Pamela; Owen, Edward; Abraham, Matthew; La Monte, Gregory; Painter, Heather J.; Williams, Roy M.; Franco, Virginia; Linares, Maria; Arriaga, Ignacio; Bopp, Selina; Corey, Victoria C.; Gnädig, Nina F.; Coburn-Flynn, Olivia; Reimer, Christin; Gupta, Purva; Murithi, James M.; Moura, Pedro A.; Fuchs, Olivia; Sasaki, Erika; Kim, Sang W.; Teng, Christine H.; Wang, Lawrence T.; Akidil, Asl; Adjalley, Sophie; Willis, Paul A.; Siegel, Dionicio; Tanaseichuk, Olga; Zhong, Yang; Zhou, Yingyao; Llinás, Manuel; Ottilie, Sabine; Gamo, Francisco Javier; Lee, Marcus C.S.; Goldberg, Daniel E.; Fidock, David A.; Wirth, Dyann F.; Winzeler, Elizabeth A.

In: Science, Vol. 359, No. 6372, 12.01.2018, p. 191-199.

Research output: Contribution to journalArticle

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.

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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Cowell AN, Istvan ES, Lukens AK, Gomez-Lorenzo MG, Vanaerschot M, Sakata-Kato T et al. Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science. 2018 Jan 12;359(6372):191-199. https://doi.org/10.1126/science.aan4472