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However, the possibility of the emergence of genetically resistant mutants from antibiotic persister cell populations, upon continued exposure to lethal concentrations of antibiotics, remained unexplored. In the present study, we found that\n                    <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis<\/jats:named-content>\n                    cells exposed continuously to lethal concentrations of rifampin (RIF) or moxifloxacin (MXF) for prolonged durations showed killing, RIF\/MXF persistence, and regrowth phases. RIF-resistant or MXF-resistant mutants carrying clinically relevant mutations in the\n                    <jats:italic>rpoB<\/jats:italic>\n                    or\n                    <jats:italic>gyrA<\/jats:italic>\n                    gene, respectively, were found to emerge at high frequency from the RIF persistence phase population. A Luria-Delbruck fluctuation experiment using RIF-exposed\n                    <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n                    cells showed that the\n                    <jats:italic>rpoB<\/jats:italic>\n                    mutants were not preexistent in the population but were formed\n                    <jats:italic>de novo<\/jats:italic>\n                    from the RIF persistence phase population. The RIF persistence phase\n                    <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n                    cells carried elevated levels of hydroxyl radical that inflicted extensive genome-wide mutations, generating RIF-resistant mutants. Consistent with the elevated levels of hydroxyl radical-mediated genome-wide random mutagenesis, MXF-resistant\n                    <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n                    <jats:italic>gyrA de novo<\/jats:italic>\n                    mutants could be selected from the RIF persistence phase cells. Thus, unlike previous studies, which showed emergence of genetically resistant mutants upon exposure of bacteria for short durations to sublethal concentrations of antibiotics, our study demonstrates that continuous prolonged exposure of\n                    <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n                    cells to lethal concentrations of an antibiotic generates antibiotic persistence phase cells that form a reservoir for the generation of genetically resistant mutants to the same antibiotic or another antibiotic. These findings may have clinical significance in the emergence of drug-resistant tubercle bacilli.\n                  <\/jats:p>","DOI":"10.1128\/aac.01343-16","type":"journal-article","created":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T21:31:07Z","timestamp":1480368667000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":105,"title":["<i>De Novo<\/i>\n                    Emergence of Genetically Resistant Mutants of Mycobacterium tuberculosis from the Persistence Phase Cells Formed against Antituberculosis Drugs\n                    <i>In Vitro<\/i>"],"prefix":"10.1128","volume":"61","author":[{"given":"Jees","family":"Sebastian","sequence":"first","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharmada","family":"Swaminath","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmi Ravindran","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kishor","family":"Jakkala","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atul","family":"Pradhan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parthasarathi","family":"Ajitkumar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)74210-3"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2013.05.009"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1099390"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000317"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00921-12"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.112408.134306"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1229858"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.07.048"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro749"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2003.08.003"},{"key":"e_1_3_3_12_2","first-page":"1","article-title":"Tubercle bacilli in latent tuberculous lesions and in lung tissue without tuberculous lesions","volume":"4","author":"Opie EL","year":"1927","unstructured":"Opie EL AronsonJD. 1927. 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