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Phylogenetically related rifampin-resistant actinomycetes with mutations mapping to clinically dominant<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>mutations in the<jats:italic>rpoB<\/jats:italic>gene show upregulation of gene networks encoding secondary metabolites. We compared the expressed proteomes and metabolomes of two fully drug-susceptible clinical strains of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>(wild type) to those of their respective rifampin-resistant,<jats:italic>rpoB<\/jats:italic>mutant progeny strains with confirmed rifampin monoresistance following antitubercular therapy. Each of these strains was also used to infect gamma interferon- and lipopolysaccharide-activated murine J774A.1 macrophages to analyze transcriptional responses in a physiologically relevant model. Both<jats:italic>rpoB<\/jats:italic>mutants showed significant upregulation of the polyketide synthase genes<jats:italic>ppsA-ppsE<\/jats:italic>and<jats:italic>drrA<\/jats:italic>, which constitute an operon encoding multifunctional enzymes involved in the biosynthesis of phthiocerol dimycocerosate and other lipids in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>, but also of various secondary metabolites in related organisms, including antibiotics, such as erythromycin and rifamycins.<jats:italic>ppsA<\/jats:italic>(Rv2931),<jats:italic>ppsB<\/jats:italic>(Rv2932), and<jats:italic>ppsC<\/jats:italic>(Rv2933) were also found to be upregulated more than 10-fold in the Beijing<jats:italic>rpoB<\/jats:italic>mutant strain relative to its wild-type parent strain during infection of activated murine macrophages. In addition, metabolomics identified precursors of phthiocerol dimycocerosate, but not the intact molecule itself, in greater abundance in both<jats:italic>rpoB<\/jats:italic>mutant isolates. These data suggest that<jats:italic>rpoB<\/jats:italic>mutation in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>may trigger compensatory transcriptional changes in secondary metabolism genes analogous to those observed in related actinobacteria. These findings may assist in developing novel methods to diagnose and treat drug-resistant<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>infections.<\/jats:p>","DOI":"10.1128\/jb.01013-12","type":"journal-article","created":{"date-parts":[[2012,9,23]],"date-time":"2012-09-23T00:13:53Z","timestamp":1348359233000},"page":"6441-6452","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":94,"title":["Upregulation of the Phthiocerol Dimycocerosate Biosynthetic Pathway by Rifampin-Resistant,<i>rpoB<\/i>Mutant Mycobacterium tuberculosis"],"prefix":"10.1128","volume":"194","author":[{"given":"Gregory P.","family":"Bisson","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Center for Clinical Epidemiology and Biostatistics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Mehaffy","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey","family":"Broeckling","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Prenni","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalin","family":"Rifat","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desmond S.","family":"Lun","sequence":"additional","affiliation":[{"name":"Center for Computational and Integrative Biology and Department of Computer Science, Rutgers University, Camden, New Jersey, USA"},{"name":"Phenomics and Bioinformatics Research Centre and School of Mathematics and Statistics, University of South Australia, Mawson Lakes, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Burgos","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, University of New Mexico, Albuquerque, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew","family":"Weissman","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petros C.","family":"Karakousis","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Dobos","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/605605"},{"key":"e_1_3_3_3_2","doi-asserted-by":"crossref","unstructured":"Astarie-DequekerC. 2009. 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