{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:04:22Z","timestamp":1782281062460,"version":"3.54.5"},"posted":{"date-parts":[[2026,1,30]]},"group-title":"Biochemistry","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gates Foundation","award":["INV-002563"],"award-info":[{"award-number":["INV-002563"]}]},{"name":"Gates Foundation","award":["INV001727"],"award-info":[{"award-number":["INV001727"]}]},{"name":"Gates Foundation","award":["INV-055896"],"award-info":[{"award-number":["INV-055896"]}]},{"name":"Gates Foundation","award":["INV-002178"],"award-info":[{"award-number":["INV-002178"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Globally,\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  remains a significant disease burden. Although effective treatment regimens exist, drug resistance continues to emerge. This clinical resistance, combined with side effects and protracted treatment times from the current front-line therapies, means there is a need to identify novel agents to combat this disease. Here we report on a new chemical series, identified by whole-cell phenotypic growth inhibition screening that demonstrates significant activity across multiple media. Mode of action studies indicate that this series targets the same biological pathway as Ethambutol (EMB), a drug used in the current frontline treatment of tuberculosis. Screening selected analogues against clinical isolates, resistant to EMB, demonstrated differential sensitivity both across the molecules and against the different specific resistant mutations. The data obtained suggests that this series has potential to be developed into a viable, alternative to EMB.\n                <\/jats:p>\n                <jats:sec id=\"s7\">\n                  <jats:title>TOC figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"702510v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.30.702510","type":"posted-content","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T03:40:24Z","timestamp":1769830824000},"source":"Crossref","is-referenced-by-count":0,"title":["Identification and Evaluation of dibasic piperidines as novel cell wall inhibitors against\n                  <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.64898","author":[{"given":"Claire","family":"Naylor","sequence":"first","affiliation":[{"name":"Drug Discovery Unit, Faculty of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3586-0284","authenticated-orcid":false,"given":"Gareth A","family":"Prosser","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, Faculty of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Bayliss","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, Faculty of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3642-1793","authenticated-orcid":false,"given":"Lila","family":"Berle","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 9000 Rockville Pike, Bethesda, Maryland, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1108-3852","authenticated-orcid":false,"given":"Joshua B","family":"Wallach","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3152-5785","authenticated-orcid":false,"given":"Heather","family":"Kim","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5762-8470","authenticated-orcid":false,"given":"Rodrigo Aguilera","family":"Olvera","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Thompson","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, Faculty of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8702-9102","authenticated-orcid":false,"given":"Thomas R","family":"Ioerger","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Simpson","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, Faculty of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Casanueva","sequence":"additional","affiliation":[{"name":"Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Guijarro-Lopez","sequence":"additional","affiliation":[{"name":"Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8536-0130","authenticated-orcid":false,"given":"Kevin D.","family":"Read","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, Faculty of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0397-245X","authenticated-orcid":false,"given":"Paul G","family":"Wyatt","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, Faculty of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4445-7219","authenticated-orcid":false,"given":"Dirk","family":"Schnappinger","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2927-270X","authenticated-orcid":false,"given":"Clifton E","family":"Barry","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 9000 Rockville Pike, Bethesda, Maryland, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5054-4792","authenticated-orcid":false,"given":"Simon R","family":"Green","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, Faculty of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4333-206X","authenticated-orcid":false,"given":"Helena I","family":"Boshoff","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 9000 Rockville Pike, Bethesda, Maryland, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6218-0092","authenticated-orcid":false,"given":"Laura A T","family":"Cleghorn","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, Faculty of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020511535436000_2026.01.30.702510v1.1","unstructured":"WHO Global tuberculosis report 2025; ISBN 978-92-4-011693-1; World Health Organization: Geneva (Switzerland), 2025."},{"key":"2026020511535436000_2026.01.30.702510v1.2","unstructured":"WHO WHO consolidated guidelines on tuberculosis: module 4: treatment and care; ISBN: 978-92-4-010724-3; World Health Organization: Geneva (Switzerland), 2025."},{"key":"2026020511535436000_2026.01.30.702510v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2024.103955"},{"key":"2026020511535436000_2026.01.30.702510v1.4","unstructured":"WHO WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update; ISBN 978-92-4-006312-9; World Health Organization: Geneva (Switzerland), 2022."},{"issue":"3","key":"2026020511535436000_2026.01.30.702510v1.5","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1021\/acsinfecdis.4c00808","article-title":"Identification of a Series Containing a Pentafluorophenyl Moiety That Targets Pks13 to Inhibit Growth of Mycobacterium tuberculosis","volume":"11","year":"2025","journal-title":"ACS Inf. Dis"},{"key":"2026020511535436000_2026.01.30.702510v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2013.09.003"},{"key":"2026020511535436000_2026.01.30.702510v1.7","doi-asserted-by":"publisher","DOI":"10.1128\/JB.182.7.1802-1811.2000"},{"key":"2026020511535436000_2026.01.30.702510v1.8","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01178-16"},{"key":"2026020511535436000_2026.01.30.702510v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00731-y"},{"key":"2026020511535436000_2026.01.30.702510v1.10","unstructured":"Stop_TB_Partnership Clinical Pipeline. https:\/\/www.newtbdrugs.org\/pipeline\/clinical. 11."},{"key":"2026020511535436000_2026.01.30.702510v1.11","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01357-08"},{"key":"2026020511535436000_2026.01.30.702510v1.12","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03002-15"},{"key":"2026020511535436000_2026.01.30.702510v1.13","first-page":"951706","article-title":"Mutations Found in embCAB, embR, and ubiA Genes of Ethambutol-Sensitive and -Resistant Mycobacterium tuberculosis Clinical Isolates from China","volume":"2015","year":"2015","journal-title":"BioMed Research International"},{"key":"2026020511535436000_2026.01.30.702510v1.14","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-091014-104121"},{"key":"2026020511535436000_2026.01.30.702510v1.15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504068200"},{"key":"2026020511535436000_2026.01.30.702510v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2021.06.033"},{"issue":"4","key":"2026020511535436000_2026.01.30.702510v1.17","doi-asserted-by":"crossref","first-page":"16274","DOI":"10.1038\/nmicrobiol.2016.274","article-title":"Programmable transcriptional repression in mycobacteria using an orthogonal CRISPR interference platform","volume":"2","year":"2017","journal-title":"Nat. Microbiol"},{"key":"2026020511535436000_2026.01.30.702510v1.18","unstructured":"WHO, Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance. 2nd ed.; World Health Organisation: Geneva (Switzerland), 2023."},{"key":"2026020511535436000_2026.01.30.702510v1.19","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12252"},{"issue":"4","key":"2026020511535436000_2026.01.30.702510v1.20","doi-asserted-by":"crossref","first-page":"e0158623","DOI":"10.1128\/aac.01586-23","article-title":"Ethambutol and meropenem\/clavulanate synergy promotes enhanced extracellular and intracellular killing of Mycobacterium tuberculosis","volume":"68","year":"2024","journal-title":"Antimicrob Agents Chemother"},{"key":"2026020511535436000_2026.01.30.702510v1.21","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01423-09"},{"key":"2026020511535436000_2026.01.30.702510v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-017-0029-0"},{"key":"2026020511535436000_2026.01.30.702510v1.23","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba9102"},{"key":"2026020511535436000_2026.01.30.702510v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2014.12.002"},{"key":"2026020511535436000_2026.01.30.702510v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2743"},{"key":"2026020511535436000_2026.01.30.702510v1.26","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00883"},{"key":"2026020511535436000_2026.01.30.702510v1.27","doi-asserted-by":"publisher","DOI":"10.1021\/cb300112x"},{"key":"2026020511535436000_2026.01.30.702510v1.28","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00166-10"},{"key":"2026020511535436000_2026.01.30.702510v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"issue":"6","key":"2026020511535436000_2026.01.30.702510v1.30","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/s41564-022-01130-y","article-title":"CRISPRi chemical genetics and comparative genomics identify genes mediating drug potency in Mycobacterium tuberculosis","volume":"7","year":"2022","journal-title":"Nat. Microbiol"},{"key":"2026020511535436000_2026.01.30.702510v1.31","doi-asserted-by":"crossref","unstructured":"Davis, S. H. ; Mathieson, M. ; Buchanan, K. I. ; Dawson, A. ; Smith, A. ; Cocco, M. ; Tamaki, F. K. ; Post, J. M. ; Baraga\u00f1a, B. ; Jansen, C. ; Kiczun, M. ; Zuccotto, F. ; Wood, G. ; Scullion, P. ; Ray, P. C. ; Epemolu, O. ; Lopez-Rom\u00e1n, E. M. ; L\u00f3pez, L. G. ; Engelhart, C. A. ; Kim, J. ; Pino, P. A. ; Schnappinger, D. ; Read, K. D. ; Encinas, L. ; Bates, R. H. ; Wyatt, P. G. ; Green, S. R. ; Cleghorn, L. A. T. , Design and Development of Lysyl tRNA Synthetase Inhibitors, for the Treatment of Tuberculosis. J Med Chem 2025.","DOI":"10.1101\/2025.05.13.646596"},{"key":"2026020511535436000_2026.01.30.702510v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33736-5"},{"key":"2026020511535436000_2026.01.30.702510v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/nature14451"},{"issue":"17","key":"2026020511535436000_2026.01.30.702510v1.34","doi-asserted-by":"crossref","first-page":"7284","DOI":"10.1021\/acs.jmedchem.7b00463","article-title":"Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi","volume":"60","year":"2017","journal-title":"J Med Chem"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.30.702510","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:14:56Z","timestamp":1782278096000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.30.702510"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":34,"URL":"https:\/\/doi.org\/10.64898\/2026.01.30.702510","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1021\/acsinfecdis.6c00123","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2026,1,30]]},"subtype":"preprint"}}