title: High Persister Mutants in Mycobacterium tuberculosis.
abstract: Mycobacterium tuberculosis forms drug-tolerant persister cells that are the probable cause of its recalcitrance to antibiotic therapy. While genetically identical to the rest of the population, persisters are dormant, which protects them from killing by bactericidal antibiotics. The mechanism of persister formation in M. tuberculosis is not well understood. In this study, we selected for high persister (hip) mutants and characterized them by whole genome sequencing and transcriptome analysis. In parallel, we identified and characterized clinical isolates that naturally produce high levels of persisters. We compared the hip mutants obtained in vitro with clinical isolates to identify candidate persister genes. Genes involved in lipid biosynthesis, carbon metabolism, toxin-antitoxin systems, and transcriptional regulators were among those identified. We also found that clinical hip isolates exhibited greater ex vivo survival than the low persister isolates. Our data suggest that M. tuberculosis persister formation involves multiple pathways, and hip mutants may contribute to the recalcitrance of the infection.
authors.affiliation: Department of Biology, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Torrey
authors.affiliation: Department of Biology, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: Iris
authors.initials: I
authors.lastname: Keren
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.affiliation: International Tuberculosis Research Center, Changwon, Republic of Korea.
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biology, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: Kim
authors.initials: K
authors.lastname: Lewis
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D016680:Genome, Bacterial; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000302:isolation & purification; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014376:Tuberculosis / Q000382:microbiology / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents