Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

Simon R. Green; Susan H. Davis; Sebastian Damerow; Curtis A. Engelhart; Michael Mathieson; Beatriz Baragaña; David A. Robinson; Jevgenia Tamjar; Alice Dawson; Fabio K. Tamaki; Kirsteen I. Buchanan; John Post; Karen Dowers; Sharon M. Shepherd; Chimed Jansen; Fabio Zuccotto; Ian H. Gilbert; Ola Epemolu; Jennifer Riley; Laste Stojanovski; Maria Osuna-Cabello; Esther Pérez-Herrán; María José Rebollo; Laura Guijarro López; Patricia Casado Castro; Isabel Camino; Heather C. Kim; James M. Bean; Navid Nahiyaan; Kyu Y. Rhee; Qinglan Wang; Vee Y. Tan; Helena I.M. Boshoff; Paul J. Converse; Si Yang Li; Yong S. Chang; Nader Fotouhi; Anna M. Upton; Eric L. Nuermberger; Dirk Schnappinger; Kevin D. Read; Lourdes Encinas; Robert H. Bates; Paul G. Wyatt; Laura A.T. Cleghorn

doi:10.1038/s41467-022-33736-5

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

Simon R. Green, Susan H. Davis, Sebastian Damerow, Curtis A. Engelhart, Michael Mathieson, Beatriz Baragaña, David A. Robinson, Jevgenia Tamjar, Alice Dawson, Fabio K. Tamaki, Kirsteen I. Buchanan, John Post, Karen Dowers, Sharon M. Shepherd, Chimed Jansen, Fabio Zuccotto, Ian H. Gilbert, Ola Epemolu, Jennifer Riley, Laste StojanovskiMaria Osuna-Cabello, Esther Pérez-Herrán, María José Rebollo, Laura Guijarro López, Patricia Casado Castro, Isabel Camino, Heather C. Kim, James M. Bean, Navid Nahiyaan, Kyu Y. Rhee, Qinglan Wang, Vee Y. Tan, Helena I.M. Boshoff, Paul J. Converse, Si Yang Li, Yong S. Chang, Nader Fotouhi, Anna M. Upton, Eric L. Nuermberger, Dirk Schnappinger, Kevin D. Read, Lourdes Encinas, Robert H. Bates, Paul G. Wyatt, Laura A.T. Cleghorn

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.

Original language	English (US)
Article number	5992
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33736-5
State	Published - Dec 2022

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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10.1038/s41467-022-33736-5

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Green, S. R., Davis, S. H., Damerow, S., Engelhart, C. A., Mathieson, M., Baragaña, B., Robinson, D. A., Tamjar, J., Dawson, A., Tamaki, F. K., Buchanan, K. I., Post, J., Dowers, K., Shepherd, S. M., Jansen, C., Zuccotto, F., Gilbert, I. H., Epemolu, O., Riley, J., ... Cleghorn, L. A. T. (2022). Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs. Nature communications, 13(1), Article 5992. https://doi.org/10.1038/s41467-022-33736-5

Green, SR, Davis, SH, Damerow, S, Engelhart, CA, Mathieson, M, Baragaña, B, Robinson, DA, Tamjar, J, Dawson, A, Tamaki, FK, Buchanan, KI, Post, J, Dowers, K, Shepherd, SM, Jansen, C, Zuccotto, F, Gilbert, IH, Epemolu, O, Riley, J, Stojanovski, L, Osuna-Cabello, M, Pérez-Herrán, E, Rebollo, MJ, Guijarro López, L, Casado Castro, P, Camino, I, Kim, HC, Bean, JM, Nahiyaan, N, Rhee, KY, Wang, Q, Tan, VY, Boshoff, HIM, Converse, PJ, Li, SY, Chang, YS, Fotouhi, N, Upton, AM, Nuermberger, EL, Schnappinger, D, Read, KD, Encinas, L, Bates, RH, Wyatt, PG & Cleghorn, LAT 2022, 'Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs', Nature communications, vol. 13, no. 1, 5992. https://doi.org/10.1038/s41467-022-33736-5

@article{c4e6cc97efa84f6397b17ceb1b8d1ebf,

title = "Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs",

abstract = "Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.",

author = "Green, {Simon R.} and Davis, {Susan H.} and Sebastian Damerow and Engelhart, {Curtis A.} and Michael Mathieson and Beatriz Baraga{\~n}a and Robinson, {David A.} and Jevgenia Tamjar and Alice Dawson and Tamaki, {Fabio K.} and Buchanan, {Kirsteen I.} and John Post and Karen Dowers and Shepherd, {Sharon M.} and Chimed Jansen and Fabio Zuccotto and Gilbert, {Ian H.} and Ola Epemolu and Jennifer Riley and Laste Stojanovski and Maria Osuna-Cabello and Esther P{\'e}rez-Herr{\'a}n and Rebollo, {Mar{\'i}a Jos{\'e}} and {Guijarro L{\'o}pez}, Laura and {Casado Castro}, Patricia and Isabel Camino and Kim, {Heather C.} and Bean, {James M.} and Navid Nahiyaan and Rhee, {Kyu Y.} and Qinglan Wang and Tan, {Vee Y.} and Boshoff, {Helena I.M.} and Converse, {Paul J.} and Li, {Si Yang} and Chang, {Yong S.} and Nader Fotouhi and Upton, {Anna M.} and Nuermberger, {Eric L.} and Dirk Schnappinger and Read, {Kevin D.} and Lourdes Encinas and Bates, {Robert H.} and Wyatt, {Paul G.} and Cleghorn, {Laura A.T.}",

note = "Funding Information: We thank Lucy Ellis, Nicole Mutter, Fred Simeons, Yoko Shishikura, Liam Ferguson, Lorna Campbell, Alex Cookson, Kirsty Cookson, Desiree Zeller, and Kieran Cartmill, for technical assistance. Gail Louw provided strains resistant to bedaquiline or pretominid. This work was funded in part by an award to P.G.W. from the Bill and Melinda Gates Foundation (OPP1066891 and OPP1191579) and Wellcome Trust, (100195/Z/12/Z); awards to D.S. from B&MGF (INV-010616 and INV-004761); awards to K.Y.R. from B&MGF (INV-004709 and OPP 1177930); E.L.N. was supported by TB Alliance with funds from Australia Aid, B&MGF (OPP1129600), the Germany Federal Ministry of Education and Research through KfW, Global Health Innovative Technology Fund, Irish Aid, Netherlands Ministry of Foreign Affairs and UK Aid. Work was also funded in part, by the Intramural Research Program of the NIH, NIAID. We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology. The authors would like to thank Diamond Light Source (proposal mx14980; beamlines I04 and I04-1) and SOLEIL (proposal 20181042; beamline Proxima2A) for beamtime, and the staff at the beamlines for assistance with crystal testing and data collection. The authors would like to thank Peter Warner of the B&MGF for advice, support, and encouragement. Funding Information: We thank Lucy Ellis, Nicole Mutter, Fred Simeons, Yoko Shishikura, Liam Ferguson, Lorna Campbell, Alex Cookson, Kirsty Cookson, Desiree Zeller, and Kieran Cartmill, for technical assistance. Gail Louw provided strains resistant to bedaquiline or pretominid. This work was funded in part by an award to P.G.W. from the Bill and Melinda Gates Foundation (OPP1066891 and OPP1191579) and Wellcome Trust, (100195/Z/12/Z); awards to D.S. from B&MGF (INV-010616 and INV-004761); awards to K.Y.R. from B&MGF (INV-004709 and OPP 1177930); E.L.N. was supported by TB Alliance with funds from Australia Aid, B&MGF (OPP1129600), the Germany Federal Ministry of Education and Research through KfW, Global Health Innovative Technology Fund, Irish Aid, Netherlands Ministry of Foreign Affairs and UK Aid. Work was also funded in part, by the Intramural Research Program of the NIH, NIAID. We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology. The authors would like to thank Diamond Light Source (proposal mx14980; beamlines I04 and I04-1) and SOLEIL (proposal 20181042; beamline Proxima2A) for beamtime, and the staff at the beamlines for assistance with crystal testing and data collection. The authors would like to thank Peter Warner of the B&MGF for advice, support, and encouragement. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-33736-5",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

AU - Green, Simon R.

AU - Davis, Susan H.

AU - Damerow, Sebastian

AU - Engelhart, Curtis A.

AU - Mathieson, Michael

AU - Baragaña, Beatriz

AU - Robinson, David A.

AU - Tamjar, Jevgenia

AU - Dawson, Alice

AU - Tamaki, Fabio K.

AU - Buchanan, Kirsteen I.

AU - Post, John

AU - Dowers, Karen

AU - Shepherd, Sharon M.

AU - Jansen, Chimed

AU - Zuccotto, Fabio

AU - Gilbert, Ian H.

AU - Epemolu, Ola

AU - Riley, Jennifer

AU - Stojanovski, Laste

AU - Osuna-Cabello, Maria

AU - Pérez-Herrán, Esther

AU - Rebollo, María José

AU - Guijarro López, Laura

AU - Casado Castro, Patricia

AU - Camino, Isabel

AU - Kim, Heather C.

AU - Bean, James M.

AU - Nahiyaan, Navid

AU - Rhee, Kyu Y.

AU - Wang, Qinglan

AU - Tan, Vee Y.

AU - Boshoff, Helena I.M.

AU - Converse, Paul J.

AU - Li, Si Yang

AU - Chang, Yong S.

AU - Fotouhi, Nader

AU - Upton, Anna M.

AU - Nuermberger, Eric L.

AU - Schnappinger, Dirk

AU - Read, Kevin D.

AU - Encinas, Lourdes

AU - Bates, Robert H.

AU - Wyatt, Paul G.

AU - Cleghorn, Laura A.T.

N1 - Funding Information: We thank Lucy Ellis, Nicole Mutter, Fred Simeons, Yoko Shishikura, Liam Ferguson, Lorna Campbell, Alex Cookson, Kirsty Cookson, Desiree Zeller, and Kieran Cartmill, for technical assistance. Gail Louw provided strains resistant to bedaquiline or pretominid. This work was funded in part by an award to P.G.W. from the Bill and Melinda Gates Foundation (OPP1066891 and OPP1191579) and Wellcome Trust, (100195/Z/12/Z); awards to D.S. from B&MGF (INV-010616 and INV-004761); awards to K.Y.R. from B&MGF (INV-004709 and OPP 1177930); E.L.N. was supported by TB Alliance with funds from Australia Aid, B&MGF (OPP1129600), the Germany Federal Ministry of Education and Research through KfW, Global Health Innovative Technology Fund, Irish Aid, Netherlands Ministry of Foreign Affairs and UK Aid. Work was also funded in part, by the Intramural Research Program of the NIH, NIAID. We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. The authors would like to thank Diamond Light Source (proposal mx14980; beamlines I04 and I04-1) and SOLEIL (proposal 20181042; beamline Proxima2A) for beamtime, and the staff at the beamlines for assistance with crystal testing and data collection. The authors would like to thank Peter Warner of the B&MGF for advice, support, and encouragement. Funding Information: We thank Lucy Ellis, Nicole Mutter, Fred Simeons, Yoko Shishikura, Liam Ferguson, Lorna Campbell, Alex Cookson, Kirsty Cookson, Desiree Zeller, and Kieran Cartmill, for technical assistance. Gail Louw provided strains resistant to bedaquiline or pretominid. This work was funded in part by an award to P.G.W. from the Bill and Melinda Gates Foundation (OPP1066891 and OPP1191579) and Wellcome Trust, (100195/Z/12/Z); awards to D.S. from B&MGF (INV-010616 and INV-004761); awards to K.Y.R. from B&MGF (INV-004709 and OPP 1177930); E.L.N. was supported by TB Alliance with funds from Australia Aid, B&MGF (OPP1129600), the Germany Federal Ministry of Education and Research through KfW, Global Health Innovative Technology Fund, Irish Aid, Netherlands Ministry of Foreign Affairs and UK Aid. Work was also funded in part, by the Intramural Research Program of the NIH, NIAID. We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. The authors would like to thank Diamond Light Source (proposal mx14980; beamlines I04 and I04-1) and SOLEIL (proposal 20181042; beamline Proxima2A) for beamtime, and the staff at the beamlines for assistance with crystal testing and data collection. The authors would like to thank Peter Warner of the B&MGF for advice, support, and encouragement. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.

AB - Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.

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UR - http://www.scopus.com/inward/citedby.url?scp=85139718046&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-33736-5

DO - 10.1038/s41467-022-33736-5

M3 - Article

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AN - SCOPUS:85139718046

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5992

ER -

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

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