ArticleNature communications2022
Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.
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Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24citing papers in PubMed
2.3field-weighted citation impact, top 10% of its field
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Who cites it
24 citing papers in PubMed, 30 citations in OpenAlex.
- Atomic-Level Structures Reveal How a Repurposed 3‑Aminopyrazine-2-carboxamide Scaffold InhibitsACS omega · 2026Article
- In Vivo Efficacy and Biochemical Target Engagement of a Chromene-Based Inhibitor of Trypanosoma cruzi Lysyl-tRNA Synthetase.Journal of medicinal chemistry · 2026Article
- New hit compounds againstAntimicrobial agents and chemotherapy · 2026Article
- Identification and Evaluation of Dibasic Piperidines as Cell Wall Inhibitors againstACS infectious diseases · 2026Article
- Structure-Guided Optimization of Novel Inhibitors ofJournal of medicinal chemistry · 2026Article
- Genome scale CRISPRi reveals both shared and strain-specific vulnerabilities in genetically diverse drug-resistant strains of Mycobacterium tuberculosis.Nature communications · 2026Article
- Identification and Evaluation of dibasic piperidines as novel cell wall inhibitors againstbioRxiv : the preprint server for biology · 2026Article
- Integration of multi-modal measurements identifies critical mechanisms of tuberculosis drug action.Cell systems · 2025Article
- Design and Development of Lysyl tRNA Synthetase Inhibitors, for the Treatment of Tuberculosis.Journal of medicinal chemistry · 2025Article
- Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease.Science translational medicine · 2025Article
- Aminoisothiazolamides, a new class of potent inhibitors of lysyl-tRNA synthetase.Pest management science · 2025Article
- Different chemical scaffolds bind to L-phe site in Mycobacterium tuberculosis Phe-tRNA synthetase.European journal of medicinal chemistry · 2025Article
- Identification of a Series Containing a Pentafluorophenyl Moiety That Targets Pks13 to Inhibit Growth ofACS infectious diseases · 2025Article
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- Structure-guided conversion from an anaplastic lymphoma kinase inhibitor into Plasmodium lysyl-tRNA synthetase selective inhibitors.Communications biology · 2024Article
- Mycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin.Nature communications · 2024Article
- Inhibitors of the Thioesterase Activity ofACS infectious diseases · 2024Article
- Therapeutic developments for tuberculosis and nontuberculous mycobacterial lung disease.Nature reviews. Drug discovery · 2024Review
- Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity.Journal of medicinal chemistry · 2023Article
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Authors and funding
45 authors at 7 institutions in 3 countries.
Simon R GreenDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.ORCID 0000-0001-5054-4792
Susan H DavisDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Sebastian DamerowDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Curtis A EngelhartDept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.ORCID 0000-0002-9324-5861
Michael MathiesonDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Beatriz BaragañaDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.ORCID 0000-0002-0959-1113
David A RobinsonDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.ORCID 0000-0003-1979-5918
Jevgenia TamjarDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Alice DawsonDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.ORCID 0000-0002-3284-553X
Fabio K TamakiDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Kirsteen I BuchananDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
John PostDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Karen DowersDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Sharon M ShepherdDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Chimed JansenDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Fabio ZuccottoDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Ian H GilbertDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.ORCID 0000-0002-5238-1314
Ola EpemoluDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Jennifer RileyDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Laste StojanovskiDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Maria Osuna-CabelloDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Esther Pérez-HerránGlobal Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
María José RebolloGlobal Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
Laura Guijarro LópezGlobal Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
Patricia Casado CastroGlobal Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.ORCID 0000-0002-8999-2063
Isabel CaminoGlobal Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
Heather C KimDept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.ORCID 0000-0003-3152-5785
James M BeanSloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA.ORCID 0000-0001-6733-5794
Navid NahiyaanDept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Kyu Y RheeDept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.ORCID 0000-0003-4582-2895
Qinglan WangTuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 9000 Rockville Pike, Bethesda, MD, USA.
Vee Y TanTuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 9000 Rockville Pike, Bethesda, MD, USA.
Helena I M BoshoffTuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 9000 Rockville Pike, Bethesda, MD, USA.ORCID 0000-0002-4333-206X
Paul J ConverseCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Si-Yang LiCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Yong S ChangCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Nader FotouhiGlobal Alliance for TB Drug Development, New York, NY, USA.
Anna M UptonGlobal Alliance for TB Drug Development, New York, NY, USA.
Eric L NuermbergerCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.ORCID 0000-0003-1440-9889
Dirk SchnappingerDept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.ORCID 0000-0002-4445-7219
Kevin D ReadDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.ORCID 0000-0002-8536-0130
Lourdes EncinasGlobal Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
Robert H BatesGlobal Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
Paul G WyattDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Laura A T CleghornDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK. l.a.t.cleghorn@dundee.ac.uk.ORCID 0000-0001-6218-0092
University of Dundee · GBGlaxoSmithKline (Spain) · ESCornell University · USJohns Hopkins University · USNational Institutes of Health · USTB Alliance · USMemorial Sloan Kettering Cancer Center · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MNCI NIH HHS P30 CA008748Wellcome Trust 100195/Z/12/Z
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.
Indexed as
Lysine-tRNA LigaseMycobacterium tuberculosisTuberculosisAnimalsMiceLysine-tRNA Ligase
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