{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T01:25:55Z","timestamp":1782177955303,"version":"3.54.5"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T00:00:00Z","timestamp":1605225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009978","name":"Ernest Oppenheimer Memorial Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009978","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"DOI":"10.3389\/fcimb.2020.582416","type":"journal-article","created":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T05:56:05Z","timestamp":1605246965000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Biological Profiling Enables Rapid Mechanistic Classification of Phenotypic Screening Hits and Identification of KatG Activation-Dependent Pyridine Carboxamide Prodrugs With Activity Against Mycobacterium tuberculosis"],"prefix":"10.3389","volume":"10","author":[{"given":"Melissa D.","family":"Chengalroyen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Jordaan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronnett","family":"Seldon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ioerger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott G.","family":"Franzblau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Nasr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Digby F.","family":"Warner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Mizrahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,11,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1016\/j.chembiol.2012.05.020","article-title":"Pathway-selective sensitization of Mycobacterium tuberculosis for target-based whole-cell screening","volume":"19","author":"Abrahams","year":"2012","journal-title":"Chem. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1021\/cb500149m","article-title":"Rv2466c Mediates the Activation of TP053 To Kill Replicating and Non-replicating Mycobacterium tuberculosis","volume":"9","author":"Albesa-Jov\u00e9","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1128\/JB.182.7.1802-1811.2000","article-title":"Characterization of the Mycobacterium tuberculosis iniBAC promoter, a promoter that responds to cell wall biosynthesis inhibition","volume":"182","author":"Alland","year":"2000","journal-title":"J. Bacteriol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e102135","DOI":"10.1371\/journal.pone.0102135","article-title":"Acquired resistance of Mycobacterium tuberculosis to bedaquiline","volume":"9","author":"Andries","year":"2014","journal-title":"PLoS One"},{"key":"B5","doi-asserted-by":"publisher","first-page":"6182","DOI":"10.1021\/ja01604a064","article-title":"Some 5-(Oxoalkyl)-2-thiohydantoins and Their Derivatives","volume":"78","author":"Archer","year":"1956","journal-title":"J. Am. Chem. Soc."},{"key":"B6","doi-asserted-by":"publisher","first-page":"6962","DOI":"10.1128\/AAC.03486-14","article-title":"Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis","volume":"58","author":"Arora","year":"2014","journal-title":"Antimicrobial Agents Chemother."},{"key":"B7","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1016\/j.tim.2017.05.007","article-title":"Antimycobacterial Metabolism: Illuminating Mycobacterium tuberculosis Biology and Drug Discovery","volume":"25","author":"Awasthi","year":"2017","journal-title":"Trends Microbiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"4459","DOI":"10.1128\/JB.183.15.4459-4467.2001","article-title":"Identification of some DNA damage-inducible genes of Mycobacterium tuberculosis: apparent lack of correlation with LexA binding","volume":"183","author":"Brooks","year":"2001","journal-title":"J. Bacteriol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3920","DOI":"10.1073\/pnas.002024599","article-title":"Complex pattern of Mycobacterium marinum gene expression during long-term granulomatous infection","volume":"99","author":"Chan","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B10","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1007\/978-1-4939-2450-9_17","article-title":"Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for Mycobacterium tuberculosis","volume":"1285","author":"Cho","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"20150506","DOI":"10.1098\/rstb.2015.0506","article-title":"Inhibiting Mycobacterium tuberculosis within and without","volume":"371","author":"Cole","year":"2016","journal-title":"Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e6077","DOI":"10.1371\/journal.pone.0006077","article-title":"A Novel In Vitro Multiple-Stress Dormancy Model for Mycobacterium tuberculosis Generates a Lipid-Loaded, Drug-Tolerant, Dormant Pathogen","volume":"4","author":"Deb","year":"2009","journal-title":"PLoS One"},{"key":"B13","doi-asserted-by":"publisher","first-page":"623","DOI":"10.3390\/app10020623","article-title":"Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3","volume":"10","author":"Degiacomi","year":"2020","journal-title":"Appl. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3532","DOI":"10.1099\/mic.0.029199-0","article-title":"Rapid and spontaneous loss of phthiocerol dimycocerosate (PDIM) from Mycobacterium tuberculosis grown in vitro: implications for virulence studies","volume":"155","author":"Domenech","year":"2009","journal-title":"Microbiology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"104974","DOI":"10.1016\/j.ejps.2019.104974","article-title":"New isoniazid derivatives with improved pharmaco-toxicological profile: Obtaining, characterization and biological evaluation","volume":"137","author":"Dragostin","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.mib.2018.02.006","article-title":"Priming the tuberculosis drug pipeline: new antimycobacterial targets and agents","volume":"45","author":"Evans","year":"2018","journal-title":"Curr. Opin. Microbiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"10510","DOI":"10.1073\/pnas.1818009116","article-title":"Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis","volume":"116","author":"Flentie","year":"2019","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.tube.2012.07.003","article-title":"Comprehensive analysis of methods used for the evaluation of compounds against Mycobacterium tuberculosis","volume":"92","author":"Franzblau","year":"2012","journal-title":"Tuberculosis"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/microbiolspec.TBTB1122-0031-2016","article-title":"Targeting Phenotypically Tolerant Mycobacterium tuberculosis","volume":"5","author":"Gold","year":"2017","journal-title":"Microbiol. Spectr."},{"key":"B20","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1007\/978-1-4939-2450-9_18","article-title":"A multi-stress model for high throughput screening against non-replicating Mycobacterium tuberculosis","volume":"1285","author":"Gold","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2224","DOI":"10.1021\/cb4004817","article-title":"Identification of Novel Inhibitors of Nonreplicating Mycobacterium tuberculosis Using a Carbon Starvation Model","volume":"8","author":"Grant","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2979","DOI":"10.1128\/AAC.00037-14","article-title":"Cross-resistance between clofazimine and bedaquiline through upregulation of MmpL5 in Mycobacterium tuberculosis","volume":"58","author":"Hartkoorn","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00275","article-title":"The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against Tuberculosis","volume":"8","author":"Huang","year":"2018","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e75245","DOI":"10.1371\/journal.pone.0075245","article-title":"Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis","volume":"8","author":"Ioerger","year":"2013","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/s41586-019-1315-z","article-title":"Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes","volume":"571","author":"Johnson","year":"2019","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/nprot.2015.053","article-title":"The Phyre2 web portal for protein modeling, prediction and analysis","volume":"10","author":"Kelley","year":"2015","journal-title":"Nat. Protoc."},{"key":"B27","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1111\/j.1365-2958.2012.08199.x","article-title":"Meropenem inhibits D,D-carboxypeptidase activity in Mycobacterium tuberculosis","volume":"86","author":"Kumar","year":"2012","journal-title":"Mol. Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4406","DOI":"10.1111\/1462-2920.12873","article-title":"Combatting bacterial infections by killing persister cells with mitomycin C","volume":"17","author":"Kwan","year":"2015","journal-title":"Environ. Microbiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.coph.2018.06.006","article-title":"Therapeutic potential of promiscuous targets in Mycobacterium tuberculosis","volume":"42","author":"Lee","year":"2018","journal-title":"Curr. Opin. Pharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"3246","DOI":"10.1038\/s41598-018-21378-x","article-title":"Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations","volume":"8","author":"Lempens","year":"2018","journal-title":"Sci. Rep."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1021\/acsinfecdis.9b00048","article-title":"Direct Inhibition of MmpL3 by Novel Antitubercular Compounds","volume":"5","author":"Li","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.3390\/app10072605","article-title":"TB Elimination Requires Discovery and Development of Transformational Agents","volume":"10","author":"Lienhardt","year":"2020","journal-title":"Appl. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"13011","DOI":"10.1002\/anie.201707324","article-title":"Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes","volume":"56","author":"Liu","year":"2017","journal-title":"Angew Chem. Int. Ed. Engl."},{"key":"B35","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.ejmech.2014.04.077","article-title":"Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity","volume":"81","author":"Martins","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1099\/mic.0.000498","article-title":"Mutations in MmpL3 alter membrane potential, hydrophobicity and antibiotic susceptibility in Mycobacterium smegmatis","volume":"163","author":"McNeil","year":"2017","journal-title":"Microbiol. (Reading Engl.)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.tube.2008.08.003","article-title":"Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL5 efflux system","volume":"89","author":"Milano","year":"2009","journal-title":"Tuberc. (Edinb)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e01338","DOI":"10.1128\/AAC.01338-17","article-title":"Susceptibility of Mycobacterium tuberculosis Cytochrome bd Oxidase Mutants to Compounds Targeting the Terminal Respiratory Oxidase, Cytochrome c","volume":"61","author":"Moosa","year":"2017","journal-title":"Antimicrobial Agents Chemother."},{"key":"B39","doi-asserted-by":"publisher","first-page":"6748","DOI":"10.1128\/AAC.01178-16","article-title":"Bioluminescent Reporters for Rapid Mechanism of Action Assessment in Tuberculosis Drug Discovery","volume":"60","author":"Naran","year":"2016","journal-title":"Antimicrobial Agents Chemother."},{"key":"B40","doi-asserted-by":"publisher","first-page":"9952","DOI":"10.1021\/acs.jmedchem.8b00883","article-title":"Discovery and Structure-Activity-Relationship Study of N-Alkyl-5-hydroxypyrimidinone Carboxamides as Novel Antitubercular Agents Targeting Decaprenylphosphoryl-\u03b2-d-ribose 2\u2019-Oxidase","volume":"61","author":"Oh","year":"2018","journal-title":"J. Med. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"art.1457","DOI":"10.3390\/molecules22091457","article-title":"Mechanochemical Synthesis and Biological Evaluation of Novel Isoniazid Derivatives with Potent Antitubercular Activity","volume":"22","author":"Oliveira","year":"2017","journal-title":"Molecules"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1943","DOI":"10.1128\/AAC.45.7.1943-1946.2001","article-title":"Search for new drugs for treatment of tuberculosis","volume":"45","author":"Orme","year":"2001","journal-title":"Antimicrobial Agents Chemother."},{"key":"B43","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1080\/17460441.2020.1707801","article-title":"In vitro drug discovery models for Mycobacterium tuberculosis relevant for host infection","volume":"15","author":"Parish","year":"2020","journal-title":"Expert Opin. Drug Discov."},{"key":"B44","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1021\/acsinfecdis.6b00103","article-title":"Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis","volume":"3","author":"Park","year":"2017","journal-title":"ACS Infect. Dis."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2403","DOI":"10.1128\/AAC.45.8.2403-2404.2001","article-title":"In vitro activities of mitomycin C against growing and hypoxic dormant tubercle bacilli","volume":"45","author":"Peh","year":"2001","journal-title":"Antimicrobial Agents Chemother."},{"key":"B46","doi-asserted-by":"publisher","first-page":"289136","DOI":"10.1155\/2012\/289136","article-title":"Antimycobacterial Activities of Novel 5-(1H-1,2,3-Triazolyl)Methyl Oxazolidinones","volume":"2012","author":"Phillips","year":"2012","journal-title":"Tuberc. Res. Treat"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.1128\/AAC.05946-11","article-title":"Functional and genetic characterization of the tap efflux pump in Mycobacterium bovis BCG","volume":"56","author":"Ramon-Garcia","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"B48","doi-asserted-by":"publisher","first-page":"13097","DOI":"10.1074\/jbc.M117.797837","article-title":"The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of Mycobacterium tuberculosis","volume":"292","author":"Rosado","year":"2017","journal-title":"J. Biol. Chem."},{"key":"B49","year":"2020"},{"key":"B50","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.drudis.2016.09.01","article-title":"Identification and validation of novel drug targets in Mycobacterium tuberculosis","volume":"22","author":"Singh","year":"2017","journal-title":"Drug Discov. Today"},{"key":"B51","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1021\/acsinfecdis.6b00102","article-title":"The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis","volume":"3","author":"Singh","year":"2017","journal-title":"ACS Infect. Dis."},{"key":"B52","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/1074-5521(95)90120-5","article-title":"Mitomycin C: small, fast and deadly (but very selective)","volume":"2","author":"Tomasz","year":"1995","journal-title":"Chem. Biol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"E2510","DOI":"10.1073\/pnas.1309171110","article-title":"Identification of a small molecule with activity against drug-resistant and persistent tuberculosis","volume":"110","author":"Wang","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B54","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1021\/acsinfecdis.7b00255","article-title":"The Expanding Diversity of Mycobacterium tuberculosis Drug Targets","volume":"4","author":"Wellington","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"B55","unstructured":"Geneva, SwitzerlandWorld Health OrganizationGlobal Tuberculosis Report 20192019"},{"key":"B56","doi-asserted-by":"publisher","first-page":"e00547","DOI":"10.1128\/AAC.00547-19","article-title":"Identification of New MmpL3 Inhibitors by Untargeted and Targeted Mutant Screens Defines MmpL3 Domains with Differential Resistance","volume":"63","author":"Williams","year":"2019","journal-title":"Antimicrobial Agents Chemother."},{"key":"B57","doi-asserted-by":"publisher","first-page":"10118","DOI":"10.1021\/acs.jmedchem.7b01347","article-title":"Novel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure-Activity Relationship and Target Identification Studies","volume":"60","author":"Wilson","year":"2017","journal-title":"J. Med. Chem."},{"key":"B58","doi-asserted-by":"publisher","first-page":"3217","DOI":"10.1128\/AAC.02410-14","article-title":"In vitro and in vivo activities of three oxazolidinones against nonreplicating Mycobacterium tuberculosis","volume":"58","author":"Zhang","year":"2014","journal-title":"Antimicrobial Agents Chemother."},{"key":"B59","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/nchembio.2259","article-title":"Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence","volume":"13","author":"Zheng","year":"2017","journal-title":"Nat. Chem. Biol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2020.582416\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T05:56:08Z","timestamp":1605246968000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2020.582416\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,13]]},"references-count":59,"alternative-id":["10.3389\/fcimb.2020.582416"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2020.582416","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,13]]},"article-number":"582416"}}