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However, the molecular mechanisms regulating phenotypic drug tolerance are largely unknown. In this study, we identified a four-gene operon in\n            <jats:named-content content-type=\"genus-species\">Streptococcus pneumoniae<\/jats:named-content>\n            that contributes to\n            <jats:underline>p<\/jats:underline>\n            henotypic\n            <jats:underline>t<\/jats:underline>\n            olerance to\n            <jats:underline>v<\/jats:underline>\n            ancomycin (\n            <jats:italic>ptv<\/jats:italic>\n            ). RNA sequencing, quantiative reverse transcriptase PCR, and transcriptional luciferase reporter experiments revealed that transcription of the\n            <jats:italic>ptv<\/jats:italic>\n            operon (consisting of\n            <jats:italic>ptvR<\/jats:italic>\n            ,\n            <jats:italic>ptvA<\/jats:italic>\n            ,\n            <jats:italic>ptvB<\/jats:italic>\n            , and\n            <jats:italic>ptvC<\/jats:italic>\n            ) is induced by exposure to vancomycin. Further investigation showed that transcription of the\n            <jats:italic>ptv<\/jats:italic>\n            operon is repressed by PtvR, a PadR family repressor. Transcriptional induction of the\n            <jats:italic>ptv<\/jats:italic>\n            operon by vancomycin was achieved by transcriptional derepression of this locus, which was mediated by PtvR. Importantly, fully derepressing\n            <jats:italic>ptvABC<\/jats:italic>\n            by deleting\n            <jats:italic>ptvR<\/jats:italic>\n            or overexpressing the\n            <jats:italic>ptv<\/jats:italic>\n            operon with an exogenous promoter significantly enhanced vancomycin tolerance. Gene deletion analysis revealed that PtvA, PtvB, and PtvC are all required for the PtvR-regulated phenotypic tolerance to vancomycin. Finally, the results of an electrophoretic mobility shift assay with recombinant PtvR showed that PtvR represses the transcription of the\n            <jats:italic>ptv<\/jats:italic>\n            operon by binding to two palindromic sequences within the\n            <jats:italic>ptv<\/jats:italic>\n            promoter. Together, the\n            <jats:italic>ptv<\/jats:italic>\n            locus represents an inducible system in\n            <jats:named-content content-type=\"genus-species\">S. pneumoniae<\/jats:named-content>\n            in response to stressful conditions, including those caused by antibiotics.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Reversible or phenotypic tolerance to antibiotics within microbial populations is associated with treatment failure of bacterial diseases, but the underlying mechanisms regulating phenotypic drug tolerance remain obscure. This study reports our finding of a multigene locus that contributes to inducible tolerance to vancomycin in\n            <jats:named-content content-type=\"genus-species\">Streptococcus pneumoniae<\/jats:named-content>\n            , an important opportunistic human pathogen. The vancomycin tolerance phenotype depends on the PtvR transcriptional repressor and three predicted membrane-associated proteins encoded by the\n            <jats:italic>ptv<\/jats:italic>\n            locus. This represents the first example of a gene locus in\n            <jats:named-content content-type=\"genus-species\">S. pneumoniae<\/jats:named-content>\n            that is responsible for antibiotic tolerance and has important implications for further understanding bacterial responses and phenotypic tolerance to antibiotic treatment in this and other pathogens.\n          <\/jats:p>","DOI":"10.1128\/jb.00054-17","type":"journal-article","created":{"date-parts":[[2017,5,9]],"date-time":"2017-05-09T00:50:18Z","timestamp":1494291018000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["Transcriptional Repressor PtvR Regulates Phenotypic Tolerance to Vancomycin in Streptococcus pneumoniae"],"prefix":"10.1128","volume":"199","author":[{"given":"Xue","family":"Liu","sequence":"first","affiliation":[{"name":"Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixing","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youfu","family":"Luo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy\/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-Willem","family":"Veening","sequence":"additional","affiliation":[{"name":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland"},{"name":"Molecular Genetics Group, Groningen Biomolecular Sciences and Biotechnology Institute, Center for Synthetic Biology, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Ren","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2319"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.03.004"},{"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":"10.1038\/nrmicro1445"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2016.34"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01651-09"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.030932-0"},{"key":"e_1_3_3_9_2","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(00)74210-3","article-title":"Treatment of staphylococcal infections with penicillin by intermittent sterilization","author":"Bigger JW","year":"1944","unstructured":"Bigger JW . 1944. 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