title: Mechanisms of Phenotypic Rifampicin Tolerance in Mycobacterium tuberculosis Beijing Genotype Strain B0/W148 Revealed by Proteomics.
abstract: The "successful" Russian clone B0/W148 of Mycobacterium tuberculosis Beijing is well-known for its capacity to develop antibiotic resistance. During treatment, resistant mutants can occur that have inheritable resistance to specific antibiotics. Next to mutations, M. tuberculosis has several mechanisms that increase their tolerance to a variety of antibiotics. Insights in the phenotypic mechanisms that contribute to drug tolerance will increase our understanding of how antibiotic resistance develops in M. tuberculosis. In this study, we examined the (phospho)proteome dynamics in M. tuberculosis Beijing strain B0/W148 when exposed to a high dose of rifampicin; one of the most potent first-line antibiotics. A total of 2,534 proteins and 191 phosphorylation sites were identified, and revealed the differential regulation of DosR regulon proteins, which are necessary for the development of a dormant phenotype that is less susceptible to antibiotics. By examining independent phenotypic markers of dormancy, we show that persisters of in vitro rifampicin exposure entered a metabolically hypoactive state, which yields rifampicin and other antibiotics largely ineffective. These new insights in the role of protein regulation and post-translational modifications during the initial phase of rifampicin treatment reveal a shortcoming in the antituberculosis regimen that is administered to 8-9 million individuals annually.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC) , Leiden 2300 RC, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Keijzer
authors.affiliation: Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment (RIVM) , Bilthoven 3720 BA, The Netherlands.
authors.forename: Arnout
authors.initials: A
authors.lastname: Mulder
authors.affiliation: Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment (RIVM) , Bilthoven 3720 BA, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: de Beer
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC) , Leiden 2300 RC, The Netherlands.
authors.forename: Arnoud H
authors.initials: AH
authors.lastname: de Ru
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC) , Leiden 2300 RC, The Netherlands.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.affiliation: Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment (RIVM) , Bilthoven 3720 BA, The Netherlands.|Departments of Pulmonary Diseases and Medical Microbiology, Radboud University Medical Center , Nijmegen 6500 HB, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D024881:Drug Resistance, Bacterial / Q000235:genetics; D005838:Genotype; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D040901:Proteomics / Q000379:methods; D018085:Regulon; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C542863:DosR protein, Mycobacterium tuberculosis; D010750:Phosphoproteins; D011494:Protein Kinases; D012293:Rifampin
keywords: Mycobacterium tuberculosis; dormancy; phosphoproteomics; quantitative proteomics; rifampicin