{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:47:45Z","timestamp":1776937665606,"version":"3.51.4"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T00:00:00Z","timestamp":1674259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China Scholarship Council and the Amis des Instituts Pasteur \u00e0 Bruxelles","award":["2021BQ011"],"award-info":[{"award-number":["2021BQ011"]}]},{"name":"Nanfang College Guangzhou","award":["2021BQ011"],"award-info":[{"award-number":["2021BQ011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Due to the Mycobacterium tuberculosis complex, including M. tuberculosis and M. bovis, tuberculosis still causes 1.6 million deaths per year. Therefore, efforts to improve tuberculosis treatment are necessary. We previously showed that the GroEL1 protein is involved in antibiotic intrinsic resistance. Indeed, the M. bovis BCG cpn60.1 gene (encoding GroEL1)-disrupted strain (\u0394cpn60.1) exhibits higher rifampicin and vancomycin susceptibility due to defective cell wall integrity. Here, we show that during hypoxia-triggered growth stasis, in the Wayne dormancy model, the mutant exhibited comparable rifampicin and ethionamide susceptibility but higher isoniazid susceptibility compared to the wild-type strain. Although the \u0394cpn60.1 strain showed compromised induction of the DosR regulon, growth stasis was achieved, but an ATP burst and a higher reactive oxygen species (ROS) production were observed in the isoniazid-treated \u0394cpn60.1 strain. GroEL1 could contribute to INH tolerance by reducing ROS.<\/jats:p>","DOI":"10.3390\/microorganisms11020286","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T03:21:54Z","timestamp":1674616914000},"page":"286","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Mycobacterium bovis BCG GroEL1 Contributes to Isoniazid Tolerance in a Dormant-Like State Model"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9183-4347","authenticated-orcid":false,"given":"Sheng","family":"Zeng","sequence":"first","affiliation":[{"name":"Microbiology, Bioorganic & Macromolecular Chemistry Research Unit, Facult\u00e9 de Pharmacie, Universit\u00e9 libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Yang","sequence":"additional","affiliation":[{"name":"Microbiology, Bioorganic & Macromolecular Chemistry Research Unit, Facult\u00e9 de Pharmacie, Universit\u00e9 libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9line","family":"Rens","sequence":"additional","affiliation":[{"name":"Microbiology, Bioorganic & Macromolecular Chemistry Research Unit, Facult\u00e9 de Pharmacie, Universit\u00e9 libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7588-5462","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Fontaine","sequence":"additional","affiliation":[{"name":"Microbiology, Bioorganic & Macromolecular Chemistry Research Unit, Facult\u00e9 de Pharmacie, Universit\u00e9 libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,21]]},"reference":[{"key":"ref_1","unstructured":"WHO (2022). Global Tuberculosis Report 2022, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S94","DOI":"10.1016\/j.ijmyco.2016.09.061","article-title":"Activity of drugs against dormant Mycobacterium tuberculosis","volume":"5","author":"Iacobino","year":"2016","journal-title":"Int. J. Mycobacteriol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1046\/j.1365-2958.2002.02779.x","article-title":"Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling","volume":"43","author":"Betts","year":"2002","journal-title":"Mol. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1128\/iai.64.6.2062-2069.1996","article-title":"An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence","volume":"64","author":"Wayne","year":"1996","journal-title":"Infect. Immun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/nrmicro.2016.34","article-title":"Distinguishing between resistance, tolerance and persistence to antibiotic treatment","volume":"14","author":"Brauner","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5881","DOI":"10.1073\/pnas.0912765107","article-title":"Dormancy contributes to the maintenance of microbial diversity","volume":"107","author":"Jones","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1126\/science.aaj2191","article-title":"Antibiotic tolerance facilitates the evolution of resistance","volume":"355","author":"Ronin","year":"2017","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13881","DOI":"10.1073\/pnas.2235848100","article-title":"The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: Adduct affinity and drug resistance","volume":"100","author":"Rawat","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e01841-18","DOI":"10.1128\/AAC.01841-18","article-title":"Isoniazid bactericidal activity involves electron transport chain perturbation","volume":"63","author":"Zeng","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4218","DOI":"10.1038\/s41467-018-06667-3","article-title":"Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription","volume":"9","author":"Zhu","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1027394","DOI":"10.3389\/fcimb.2022.1027394","article-title":"The evolving biology of Mycobacterium tuberculosis drug resistance","volume":"12","author":"Jones","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Baek, S.H., Li, A.H., and Sassetti, C.M. (2011). Metabolic regulation of mycobacterial growth and antibiotic sensitivity. PLoS Biol., 9.","DOI":"10.1371\/journal.pbio.1001065"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1099\/mic.0.28993-0","article-title":"Identification of a diacylglycerol acyltransferase gene involved in accumulation of triacylglycerol in Mycobacterium tuberculosis under stress","volume":"152","author":"Sirakova","year":"2006","journal-title":"Microbiology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8667","DOI":"10.1038\/s41598-019-45164-5","article-title":"Nitrogen deprivation induces triacylglycerol accumulation, drug tolerance and hypervirulence in mycobacteria","volume":"9","author":"Santucci","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4306","DOI":"10.1038\/ncomms5306","article-title":"Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis","volume":"5","author":"Nandakumar","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e0048022","DOI":"10.1128\/mbio.00480-22","article-title":"Adenosine awakens metabolism to enhance growth-independent killing of tolerant and persister bacteria across multiple classes of antibiotics","volume":"13","author":"Kitzenberg","year":"2022","journal-title":"MBio"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4495","DOI":"10.1073\/pnas.1704376114","article-title":"Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis","volume":"114","author":"Vilcheze","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6760","DOI":"10.1128\/JB.184.24.6760-6767.2002","article-title":"Mycobacterium bovis BCG response regulator essential for hypoxic dormancy","volume":"184","author":"Boon","year":"2002","journal-title":"J. Bacteriol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.plipres.2005.07.001","article-title":"The dimycocerosate ester polyketide virulence factors of mycobacteria","volume":"44","author":"Onwueme","year":"2005","journal-title":"Prog. Lipid Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/47042","article-title":"Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice","volume":"402","author":"Cox","year":"1999","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1128\/IAI.06370-11","article-title":"Both phthiocerol dimycocerosates and phenolic glycolipids are required for virulence of Mycobacterium marinum","volume":"80","author":"Yu","year":"2012","journal-title":"Infect. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Astarie-Dequeker, C., Le Guyader, L., Malaga, W., Seaphanh, F.K., Chalut, C., Lopez, A., and Guilhot, C. (2009). Phthiocerol dimycocerosates of M. tuberculosis participate in macrophage invasion by inducing changes in the organization of plasma membrane lipids. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000289"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e00148-17","DOI":"10.1128\/mBio.00148-17","article-title":"The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of Mycobacterium tuberculosis","volume":"8","author":"Quigley","year":"2017","journal-title":"MBio"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"fnw016","DOI":"10.1093\/femsle\/fnw016","article-title":"Pleiotropic consequences of gene knockouts in the phthiocerol dimycocerosate and phenolic glycolipid biosynthetic gene cluster of the opportunistic human pathogen Mycobacterium marinum","volume":"363","author":"Mohandas","year":"2016","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.3389\/fmicb.2019.01149","article-title":"Cpn60.1 (GroEL1) contributes to mycobacterial Crabtree effect: Implications for biofilm formation","volume":"10","author":"Zeng","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5057","DOI":"10.1128\/AAC.04856-14","article-title":"Increased Vancomycin Susceptibility in Mycobacteria: A new approach to identify synergistic activity against multidrug-resistant mycobacteria","volume":"59","author":"Soetaert","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1099\/mic.0.045120-0","article-title":"Biochemical and immunological characterization of a cpn60.1 knockout mutant of Mycobacterium bovis BCG","volume":"157","author":"Wang","year":"2011","journal-title":"Microbiology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/j.1574-6968.2008.01465.x","article-title":"Mycobacterium tuberculosis groE promoter controls the expression of the bicistronic groESL1 operon and shows differential regulation under stress conditions","volume":"292","author":"Aravindhan","year":"2009","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5596","DOI":"10.1073\/pnas.0700869104","article-title":"Genome plasticity of BCG and impact on vaccine efficacy","volume":"104","author":"Brosch","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1111\/j.1742-4658.2010.07688.x","article-title":"Delineation of the roles of FadD22, FadD26 and FadD29 in the biosynthesis of phthiocerol dimycocerosates and related compounds in Mycobacterium tuberculosis","volume":"277","author":"Simeone","year":"2010","journal-title":"FEBS J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1021\/acsomega.6b00212","article-title":"Imidazoles induce reactive oxygen species in Mycobacterium tuberculosis which is not associated with cell death","volume":"2","author":"Roberts","year":"2017","journal-title":"ACS Omega"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11568","DOI":"10.1073\/pnas.0705054104","article-title":"Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor","volume":"104","author":"Kumar","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6447","DOI":"10.1128\/JB.00978-10","article-title":"DosS responds to a reduced electron transport system to induce the Mycobacterium tuberculosis DosR regulon","volume":"192","author":"Honaker","year":"2010","journal-title":"J. Bacteriol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gonzalo-Asensio, J., Mostowy, S., Harders-Westerveen, J., Huygen, K., Hernandez-Pando, R., Thole, J., Behr, M., Gicquel, B., and Martin, C. (2008). PhoP: A missing piece in the intricate puzzle of Mycobacterium tuberculosis virulence. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003496"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1038\/s41467-019-10975-7","article-title":"Transient drug-tolerance and permanent drug-resistance rely on the trehalose-catalytic shift in Mycobacterium tuberculosis","volume":"10","author":"Lee","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e01213-19","DOI":"10.1128\/AAC.01213-19","article-title":"Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance","volume":"63","author":"Richards","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","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."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13057","DOI":"10.1074\/jbc.M808905200","article-title":"Structural insight into the heme-based redox sensing by DosS from Mycobacterium tuberculosis","volume":"284","author":"Cho","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.tube.2015.11.003","article-title":"Towards understanding the biological function of the unusual chaperonin Cpn60.1 (GroEL1) of Mycobacterium tuberculosis","volume":"97","author":"Sharma","year":"2016","journal-title":"Tuberculosis"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16022","DOI":"10.1038\/cddiscovery.2016.22","article-title":"Hypoxia and classical activation limits Mycobacterium tuberculosis survival by Akt-dependent glycolytic shift in macrophages","volume":"2","author":"Matta","year":"2016","journal-title":"Cell Death Discov."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1126\/science.272.5268.1641","article-title":"Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis","volume":"272","author":"Sherman","year":"1996","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1128\/AAC.48.7.2424-2430.2004","article-title":"Inhibition of Mycobacterium tuberculosis AhpD, an element of the peroxiredoxin defense against oxidative stress","volume":"48","author":"Koshkin","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1126\/science.1067798","article-title":"Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein","volume":"295","author":"Bryk","year":"2002","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.chom.2015.05.008","article-title":"The oxidative stress network of Mycobacterium tuberculosis reveals coordination between radical detoxification systems","volume":"17","author":"Nambi","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"12393","DOI":"10.1038\/ncomms12393","article-title":"Turning the respiratory flexibility of Mycobacterium tuberculosis against itself","volume":"7","author":"Lamprecht","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.3389\/fmicb.2018.01898","article-title":"Mycobacterial cell wall synthesis inhibitors cause lethal ATP burst","volume":"9","author":"Shetty","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2840","DOI":"10.1093\/jac\/dkw244","article-title":"Activation of type II NADH dehydrogenase by quinolinequinones mediates antitubercular cell death","volume":"71","author":"Heikal","year":"2016","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10276","DOI":"10.1074\/jbc.M110.200501","article-title":"Reduction of clofazimine by mycobacterial type 2 NADH:quinone oxidoreductase: A pathway for the generation of bactericidal levels of reactive oxygen species","volume":"286","author":"Yano","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.tim.2016.12.008","article-title":"The role of reactive oxygen species in antibiotic-mediated killing of bacteria","volume":"25","author":"Coenye","year":"2017","journal-title":"Trends Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"937970","DOI":"10.3389\/fmicb.2022.937970","article-title":"HupB, a nucleoid-associated protein, is critical for survival of Mycobacterium tuberculosis under host-mediated stresses and for enhanced tolerance to key first-line antibiotics","volume":"13","author":"Singh","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4944","DOI":"10.1093\/nar\/gkp502","article-title":"A novel nucleoid-associated protein of Mycobacterium tuberculosis is a sequence homolog of GroEL","volume":"37","author":"Basu","year":"2009","journal-title":"Nucleic Acids Res."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/2\/286\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:13:06Z","timestamp":1760119986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/2\/286"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,21]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["microorganisms11020286"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms11020286","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,21]]}}}