{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:56:22Z","timestamp":1787028982402,"version":"build-2736575974"},"reference-count":80,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T00:00:00Z","timestamp":1658016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The emergence of drug resistant Mycobacterium tuberculosis (MTB) strains has become a global public health problem, while, at the same time, there has been development of new antimicrobial agents. The main goals of this study were to determine new variants associated with drug resistance in MTB and to observe which polymorphisms emerge in MTB genomes after anti-tuberculosis treatment. We performed whole-genome sequencing of 152 MTB isolates including 70 isolates as 32 series of pre- and post-treatment MTB. Based on genotypes and phenotypic drug susceptibility, we conducted phylogenetic convergence-based genome-wide association study (GWAS) with streptomycin-, isoniazid-, rifampicin-, ethambutol-, fluoroquinolones-, and aminoglycosides-resistant MTB against susceptible ones. GWAS revealed statistically significant associations of SNPs within Rv2820c, cyp123 and indels in Rv1269c, Rv1907c, Rv1883c, Rv2407, Rv3785 genes with resistant MTB phenotypes. Comparisons of serial isolates showed that treatment induced different patterns of intra-host evolution. We found indels within Rv1435c and ppsA that were not lineage-specific. In addition, Beijing-specific polymorphisms within Rv0036c, Rv0678, Rv3433c, and dop genes were detected in post-treatment isolates. The appearance of Rv3785 frameshift insertion in 2 post-treatment strains compared to pre-treatment was also observed. We propose that the insertion within Rv3785, which was a GWAS hit, might affect cell wall biosynthesis and probably mediates a compensatory mechanism in response to treatment. These results may shed light on the mechanisms of MTB adaptation to chemotherapy and drug resistance formation.<\/jats:p>","DOI":"10.3390\/microorganisms10071440","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T01:53:22Z","timestamp":1658109202000},"page":"1440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8000-6629","authenticated-orcid":false,"given":"Denis","family":"Lagutkin","sequence":"first","affiliation":[{"name":"National Medical Research Center of Phthisiopulmonology and Infectious Diseases under the Ministry of Health of the Russian Federation, 127994 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Panova","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Phthisiopulmonology and Infectious Diseases under the Ministry of Health of the Russian Federation, 127994 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatoly","family":"Vinokurov","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Phthisiopulmonology and Infectious Diseases under the Ministry of Health of the Russian Federation, 127994 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Gracheva","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Phthisiopulmonology and Infectious Diseases under the Ministry of Health of the Russian Federation, 127994 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Samoilova","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Phthisiopulmonology and Infectious Diseases under the Ministry of Health of the Russian Federation, 127994 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Vasilyeva","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Phthisiopulmonology and Infectious Diseases under the Ministry of Health of the Russian Federation, 127994 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,17]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2021). Global Tuberculosis Report 2021."},{"key":"ref_2","unstructured":"World Health Organization (2021). WHO Global Lists of High Burden Countries for Tuberculosis (TB), TB\/HIV and TB (MDR\/RR-TB)."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/ng1047","article-title":"Functional SNPs in the lymphotoxin-\u03b1 gene that are associated with susceptibility to myocardial infarction","volume":"32","author":"Ozaki","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrg.2016.132","article-title":"Microbial genome-wide association studies: Lessons from human GWAS","volume":"18","author":"Power","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mib.2015.03.002","article-title":"The advent of genome-wide association studies for bacteria","volume":"25","author":"Chen","year":"2015","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1038\/ng.2747","article-title":"Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis","volume":"45","author":"Farhat","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1101\/gr.165415.113","article-title":"Predicting the virulence of MRSA from its genome sequence","volume":"24","author":"Laabei","year":"2014","journal-title":"Genome Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Smith, T., Wolff, K.A., and Nguyen, L. (2012). Molecular biology of drug resistance in Mycobacterium tuberculosis. Pathogenesis of Mycobacterium tuberculosis and Its Interaction with the Host Organism, Springer.","DOI":"10.1007\/82_2012_279"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e18103","DOI":"10.7554\/eLife.38200","article-title":"Compensatory evolution drives multidrug-resistant tuberculosis in central Asia","volume":"7","author":"Merker","year":"2018","journal-title":"Elife"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.tig.2012.11.005","article-title":"The heterogeneous evolution of multidrug-resistant Mycobacterium tuberculosis","volume":"29","author":"Borrell","year":"2013","journal-title":"Trends Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.tube.2016.02.004","article-title":"Longitudinal whole genome analysis of pre and post drug treatment Mycobacterium tuberculosis isolates reveals progressive steps to drug resistance","volume":"98","author":"Datta","year":"2016","journal-title":"Tuberculosis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1093\/infdis\/jiv149","article-title":"Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis","volume":"212","author":"Walter","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_13","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_14","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1093\/infdis\/jiaa625","article-title":"Dynamics of extensive drug resistance evolution of Mycobacterium tuberculosis in a single patient during 9 years of disease and treatment","volume":"225","author":"Hjort","year":"2022","journal-title":"J. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1093\/infdis\/jis601","article-title":"Dynamic population changes in Mycobacterium tuberculosis during acquisition and fixation of drug resistance in patients","volume":"206","author":"Sun","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kato-Maeda, M., Ho, C., Passarelli, B., Banaei, N., Grinsdale, J., Flores, L., Anderson, J., Murray, M., Rose, G., and Kawamura, L.M. (2013). Use of whole genome sequencing to determine the microevolution of Mycobacterium tuberculosis during an outbreak. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058235"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Merker, M., Kohl, T.A., Roetzer, A., Truebe, L., Richter, E., R\u00fcsch-Gerdes, S., Fattorini, L., Oggioni, M.R., Cox, H., and Varaine, F. (2013). Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082551"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jinf.2011.01.003","article-title":"Deep resequencing of serial sputum isolates of Mycobacterium tuberculosis during therapeutic failure due to poor compliance reveals stepwise mutation of key resistance genes on an otherwise stable genetic background","volume":"62","author":"Saunders","year":"2011","journal-title":"J. Infect."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Fursov, M.V., Shitikov, E.A., Lagutkin, D.A., Fursova, A.D., Ganina, E.A., Kombarova, T.I., Grishenko, N.S., Rudnitskaya, T.I., Bespiatykh, D.A., and Kolupaeva, N.V. (2021). MDR and Pre-XDR clinical Mycobacterium tuberculosis beijing strains: Assessment of virulence and host cytokine response in mice infectious model. Microorganisms, 9.","DOI":"10.3390\/microorganisms9081792"},{"key":"ref_20","unstructured":"(2022, June 01). FastQC. Available online: https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_21","unstructured":"(2022, June 01). Snippy. Available online: https:\/\/github.com\/tseemann\/snippy."},{"key":"ref_22","first-page":"btv566","article-title":"Qualimap 2: Advanced multi-sample quality control for high-throughput sequencing data","volume":"32","author":"Okonechnikov","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1093\/nar\/gku1196","article-title":"Rapid phylogenetic analysis of large samples of recombinant bacterial whole genome sequences using gubbins","volume":"43","author":"Croucher","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e000056","DOI":"10.1099\/mgen.0.000056","article-title":"SNP-Sites: Rapid efficient extraction of SNPs from multi-FASTA alignments","volume":"2","author":"Page","year":"2016","journal-title":"Microb. genomics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1093\/bioinformatics\/btu033","article-title":"RAxML version 8: A tool for phylogenetic analysis and post-analysis of large phylogenies","volume":"30","author":"Stamatakis","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"W293","DOI":"10.1093\/nar\/gkab301","article-title":"Interactive tree of life (ITOL) v5: An online tool for phylogenetic tree display and annotation","volume":"49","author":"Letunic","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e5895","DOI":"10.7717\/peerj.5895","article-title":"MTBseq: A comprehensive pipeline for whole genome sequence analysis of Mycobacterium tuberculosis complex isolates","volume":"2018","author":"Kohl","year":"2018","journal-title":"PeerJ"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of drosophila melanogaster strain W1118; Iso-2; Iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e000368","DOI":"10.1099\/mgen.0.000368","article-title":"Prewas: Data pre-processing for more informative bacterial gwas","volume":"6","author":"Saund","year":"2020","journal-title":"Microb. Genomics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"mgen000469","DOI":"10.1099\/mgen.0.000469","article-title":"Hogwash: Three methods for genome-wide association studies in bacteria","volume":"6","author":"Saund","year":"2020","journal-title":"Microb. Genomics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1093\/bioinformatics\/btw044","article-title":"BCFtools\/RoH: A hidden markov model approach for detecting autozygosity from next-generation sequencing data","volume":"32","author":"Narasimhan","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13718","DOI":"10.1038\/s41598-019-50078-3","article-title":"A novel ancestral Beijing sublineage of Mycobacterium tuberculosis suggests the transition site to modern beijing sublineages","volume":"9","author":"Ajawatanawong","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Martin, M., deVisch, A., Barthe, P., Turapov, O., Aydogan, T., Heriaud, L., Gracy, J., Mukamolova, G.V., Letourneur, F., and Cohen-Gonsaud, M. (2021). A Mycobacterium tuberculosis effector targets mitochondrion, controls energy metabolism and limits cytochrome c exit. bioRxiv.","DOI":"10.1101\/2021.01.31.428746"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2632","DOI":"10.1074\/mcp.M114.038380","article-title":"Disclosure of selective advantages in the \u201cmodern\u201d sublineage of the Mycobacterium tuberculosis beijing genotype family by quantitative proteomics","volume":"13","year":"2014","journal-title":"Mol. Cell. Proteom."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0079-6603(08)00808-8","article-title":"Chapter 8 The making of TRNAs and more\u2014RNase P and TRNase Z","volume":"Volume 85","author":"Hartmann","year":"2009","journal-title":"Progress in Molecular Biology and Translational Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20117","DOI":"10.1074\/jbc.M800217200","article-title":"Function and structure of a prokaryotic formylglycine-generating enzyme","volume":"283","author":"Carlson","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12911","DOI":"10.1073\/pnas.1222041110","article-title":"Sulfatase-activated fluorophores for rapid discrimination of mycobacterial species and strains","volume":"110","author":"Beatty","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sogi, K.M., Gartner, Z.J., Breidenbach, M.A., Appel, M.J., Schelle, M.W., and Bertozzi, C.R. (2013). Mycobacterium tuberculosis Rv3406 is a type II alkyl sulfatase capable of sulfate scavenging. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065080"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.gene.2007.10.017","article-title":"Genome scale portrait of CAMP-receptor protein (CRP) regulons in mycobacteria points to their role in pathogenesis","volume":"407","author":"Akhter","year":"2008","journal-title":"Gene"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.gene.2016.02.003","article-title":"Whole genome analysis of an MDR Beijing\/W strain of Mycobacterium tuberculosis with large genomic deletions associated with resistance to isoniazid","volume":"582","author":"Zhang","year":"2016","journal-title":"Gene"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kruh, N.A., Troudt, J., Izzo, A., Prenni, J., and Dobos, K.M. (2010). Portrait of a pathogen: The Mycobacterium tuberculosis proteome in vivo. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013938"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"16324","DOI":"10.1073\/pnas.2002835117","article-title":"Structural basis for the broad substrate specificity of two Acyl-CoA dehydrogenases FadE5 from mycobacteria","volume":"117","author":"Chen","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/j.1462-5822.2004.00454.x","article-title":"The Mycobacterium tuberculosis SigD sigma factor controls the expression of ribosome-associated gene products in stationary phase and is required for full virulence","volume":"7","author":"Calamita","year":"2004","journal-title":"Cell. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.tube.2008.03.001","article-title":"Characterizing septum inhibition in Mycobacterium tuberculosis for novel drug discovery","volume":"88","author":"Respicio","year":"2008","journal-title":"Tuberculosis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e00974-18","DOI":"10.1128\/AAC.00974-18","article-title":"Validation of novel Mycobacterium tuberculosis isoniazid resistance mutations not detectable by common molecular tests","volume":"62","author":"Kandler","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3389\/fmicb.2011.00105","article-title":"The response of Mycobacterium tuberculosis to reactive oxygen and nitrogen species","volume":"2","author":"Voskuil","year":"2011","journal-title":"Front. Microbiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Raman, K., and Chandra, N.M. (2008). Tuberculosis interactome analysis unravels potential pathways to drug resistance. Nat. Preced., 1.","DOI":"10.1038\/npre.2008.1674.1"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Stavrum, R., Valvatne, H., B\u00f8, T.H., Jonassen, I., Hinds, J., Butcher, P.D., and Grewal, H.M.S. (2008). Genomic diversity among Beijing and non-Beijing Mycobacterium tuberculosis isolates from myanmar. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001973"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1096\/fj.201800557RR","article-title":"Mycobacterium tuberculosis type III-A CRISPR\/Cas system CrRNA and its maturation have atypical features","volume":"33","author":"Wei","year":"2019","journal-title":"FASEB J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.meegid.2018.01.027","article-title":"The truncated Rv2820c of Mycobacterium tuberculosis Beijing family augments intracellular survival of M. smegmatis by altering cytokine profile and inhibiting NO generation","volume":"59","author":"Zhai","year":"2018","journal-title":"Infect. Genet. Evol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.micpath.2011.02.008","article-title":"Truncated Rv2820c enhances mycobacterial virulence ex vivo and in vivo","volume":"50","author":"Lam","year":"2011","journal-title":"Microb. Pathog."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41588-017-0029-0","article-title":"Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis","volume":"50","author":"Coll","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1477-5956-10-14","article-title":"Analysis of intracellular expressed proteins of Mycobacterium tuberculosis clinical isolates","volume":"10","author":"Singhal","year":"2012","journal-title":"Proteome Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1128\/IAI.70.6.2787-2795.2002","article-title":"Mycobacterium tuberculosis genes induced during infection of human macrophages","volume":"70","author":"Dubnau","year":"2002","journal-title":"Infect. Immun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.1128\/IAI.73.6.3754-3757.2005","article-title":"Responses of Mycobacterium tuberculosis to growth in the mouse lung","volume":"73","author":"Dubnau","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.chembiol.2012.11.008","article-title":"Identification of widespread adenosine nucleotide binding in Mycobacterium tuberculosis","volume":"20","author":"Ansong","year":"2013","journal-title":"Chem. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e00673-21","DOI":"10.1128\/mSystems.00673-21","article-title":"Structure-aware Mycobacterium tuberculosis functional annotation uncloaks resistance, metabolic, and virulence genes","volume":"6","author":"Modlin","year":"2021","journal-title":"mSystems"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S1097-2765(00)80376-7","article-title":"The DinB gene encodes a novel E. Coli DNA polymerase, DNA Pol IV, involved in mutagenesis","volume":"4","author":"Wagner","year":"1999","journal-title":"Mol. Cell"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Gandotra, S., Lebron, M.B., and Ehrt, S. (2010). The Mycobacterium tuberculosis proteasome active site threonine is essential for persistence yet dispensable for replication and resistance to nitric oxide. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001040"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s10930-019-09876-x","article-title":"Deciphering molecular virulence mechanism of Mycobacterium tuberculosis dop isopeptidase based on its sequence\u2013structure\u2013function linkage","volume":"39","author":"Prathiviraj","year":"2020","journal-title":"Protein J."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Muzondiwa, D., Hlanze, H., and Reva, O.N. (2021). The epistatic landscape of antibiotic resistance of different clades of Mycobacterium tuberculosis. Antibiotics, 10.","DOI":"10.3390\/antibiotics10070857"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6441","DOI":"10.1128\/JB.01013-12","article-title":"Upregulation of the phthiocerol dimycocerosate biosynthetic pathway by rifampin-resistant, RpoB mutant Mycobacterium tuberculosis","volume":"194","author":"Bisson","year":"2012","journal-title":"J. Bacteriol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1007\/s00284-012-0104-9","article-title":"Genome-wide expression profiling of the response to linezolid in Mycobacterium tuberculosis","volume":"64","author":"Liang","year":"2012","journal-title":"Curr. Microbiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.jprot.2011.08.016","article-title":"Bacterial proteins with cleaved or uncleaved signal peptides of the general secretory pathway","volume":"75","author":"Leversen","year":"2011","journal-title":"J. Proteomics"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1002\/pmic.200600853","article-title":"Comprehensive analysis of exported proteins fromMycobacterium tuberculosis H37Rv","volume":"7","author":"Berven","year":"2007","journal-title":"Proteomics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6669","DOI":"10.1128\/JB.00631-06","article-title":"Inactivation of Rv2525c, a substrate of the twin arginine translocation (Tat) system of Mycobacterium tuberculosis, increases \u03b2-Lactam susceptibility and virulence","volume":"188","author":"Demangel","year":"2006","journal-title":"J. Bacteriol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.1093\/jac\/dkx316","article-title":"Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis","volume":"72","author":"Chen","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"41246","DOI":"10.1074\/jbc.C111.310847","article-title":"Extremely conserved ATP-or ADP-dependent enzymatic system for nicotinamide nucleotide","volume":"286","author":"Marbaix","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_69","unstructured":"(2022, June 13). AlphaFold Nnr Protein Structure. Available online: https:\/\/alphafold.ebi.ac.uk\/entry\/P9WF11."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Ruesen, C., Chaidir, L., van Laarhoven, A., Dian, S., Ganiem, A.R., Nebenzahl-Guimaraes, H., Huynen, M.A., Alisjahbana, B., Dutilh, B.E., and van Crevel, R. (2018). Large-scale genomic analysis shows association between homoplastic genetic variation in Mycobacterium tuberculosis genes and meningeal or pulmonary tuberculosis. BMC Genomics, 19.","DOI":"10.1186\/s12864-018-4498-z"},{"key":"ref_72","doi-asserted-by":"crossref","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":"Tuberculosis"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e02141-18","DOI":"10.1128\/AAC.02141-18","article-title":"Clofazimine exposure in vitro selects efflux pump mutants and bedaquiline resistance","volume":"63","author":"Ismail","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1093\/jac\/dkv150","article-title":"Identification of novel mutations associated with clofazimine resistance in Mycobacterium tuberculosis","volume":"70","author":"Zhang","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"16526","DOI":"10.1074\/jbc.M113.538959","article-title":"Crystal structure of the transcriptional regulator Rv0678 of Mycobacterium tuberculosis","volume":"289","author":"Radhakrishnan","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Saeed, D.K., Shakoor, S., Razzak, S.A., Hasan, Z., Sabzwari, S.F., Azizullah, Z., Kanji, A., Nasir, A., Shafiq, S., and Ghanchi, N.K. (2022). Variants associated with bedaquiline (BDQ) resistance identified in Rv0678 and efflux pump genes in Mycobacterium tuberculosis isolates from BDQ na\u00efve TB patients in pakistan. BMC Microbiol., 22.","DOI":"10.1186\/s12866-022-02475-4"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"dkw502","DOI":"10.1093\/jac\/dkw502","article-title":"Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline","volume":"72","author":"Villellas","year":"2016","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Deshayes, C., Perrodou, E., Euphrasie, D., Frapy, E., Poch, O., Bifani, P., Lecompte, O., and Reyrat, J.M. (2008). Detecting the molecular scars of evolution in the Mycobacterium tuberculosis complex by analyzing interrupted coding sequences. BMC Evol. Biol., 8.","DOI":"10.1186\/1471-2148-8-78"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"239","DOI":"10.4149\/gpb_2011_03_239","article-title":"Investigation of ABC transporter from mycobacterial arabinogalactan biosynthetic cluster","volume":"30","author":"Kaur","year":"2011","journal-title":"Gen. Physiol. Biophys."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Islam, R., Brown, S., Taheri, A., and Dumenyo, C.K. (2019). The gene encoding NAD-dependent epimerase\/dehydratase, WcaG, affects cell surface properties, virulence, and extracellular enzyme production in the soft rot phytopathogen, pectobacterium carotovorum. Microorganisms, 7.","DOI":"10.3390\/microorganisms7060172"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/10\/7\/1440\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:52:23Z","timestamp":1760140343000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/10\/7\/1440"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,17]]},"references-count":80,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["microorganisms10071440"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms10071440","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,17]]}}}