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

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

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 and Laura A. T. Cleghorn ()
Additional contact information
Simon R. Green: University of Dundee
Susan H. Davis: University of Dundee
Sebastian Damerow: University of Dundee
Curtis A. Engelhart: Weill Cornell Medical College
Michael Mathieson: University of Dundee
Beatriz Baragaña: University of Dundee
David A. Robinson: University of Dundee
Jevgenia Tamjar: University of Dundee
Alice Dawson: University of Dundee
Fabio K. Tamaki: University of Dundee
Kirsteen I. Buchanan: University of Dundee
John Post: University of Dundee
Karen Dowers: University of Dundee
Sharon M. Shepherd: University of Dundee
Chimed Jansen: University of Dundee
Fabio Zuccotto: University of Dundee
Ian H. Gilbert: University of Dundee
Ola Epemolu: University of Dundee
Jennifer Riley: University of Dundee
Laste Stojanovski: University of Dundee
Maria Osuna-Cabello: University of Dundee
Esther Pérez-Herrán: GlaxoSmithKline
María José Rebollo: GlaxoSmithKline
Laura Guijarro López: GlaxoSmithKline
Patricia Casado Castro: GlaxoSmithKline
Isabel Camino: GlaxoSmithKline
Heather C. Kim: Weill Cornell Medical College
James M. Bean: Memorial Sloan Kettering Cancer Center
Navid Nahiyaan: Weill Cornell Medical College
Kyu Y. Rhee: Weill Cornell Medical College
Qinglan Wang: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Vee Y. Tan: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Helena I. M. Boshoff: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Paul J. Converse: Johns Hopkins University, School of Medicine
Si-Yang Li: Johns Hopkins University, School of Medicine
Yong S. Chang: Johns Hopkins University, School of Medicine
Nader Fotouhi: Global Alliance for TB Drug Development
Anna M. Upton: Global Alliance for TB Drug Development
Eric L. Nuermberger: Johns Hopkins University, School of Medicine
Dirk Schnappinger: Weill Cornell Medical College
Kevin D. Read: University of Dundee
Lourdes Encinas: GlaxoSmithKline
Robert H. Bates: GlaxoSmithKline
Paul G. Wyatt: University of Dundee
Laura A. T. Cleghorn: University of Dundee

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33736-5

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