title: Genomic and transcriptomic analysis of the streptomycin-dependent Mycobacterium tuberculosis strain 18b.
abstract: BACKGROUND
  The ability of Mycobacterium tuberculosis to establish a latent infection (LTBI) in humans confounds the treatment of tuberculosis. Consequently, there is a need to discover new therapeutic agents that can kill M. tuberculosis both during active disease and LTBI. The streptomycin-dependent strain of M. tuberculosis, 18b, provides a useful tool for this purpose since upon removal of streptomycin (STR) it enters a non-replicating state that mimics latency both in vitro and in animal models.
  
  
  RESULTS
  The 4.41 Mb genome sequence of M. tuberculosis 18b was determined and this revealed the strain to belong to clade 3 of the ancient ancestral lineage of the Beijing family. STR-dependence was attributable to insertion of a single cytosine in the 530 loop of the 16S rRNA and to a single amino acid insertion in the N-terminal domain of initiation factor 3. RNA-seq was used to understand the genetic programme activated upon STR-withdrawal and hence to gain insight into LTBI. This revealed reconfiguration of gene expression and metabolic pathways showing strong similarities between non-replicating 18b and M. tuberculosis residing within macrophages, and with the core stationary phase and microaerophilic responses.
  
  
  CONCLUSIONS
  The findings of this investigation confirm the validity of 18b as a model for LTBI, and provide insight into both the evolution of tubercle bacilli and the functioning of the ribosome.
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland. andrej.benjak@epfl.ch.
authors.forename: Andrej
authors.initials: A
authors.lastname: Benjak
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland. uplekar@gmail.com.|Current addresses: Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY, USA. uplekar@gmail.com.
authors.forename: Swapna
authors.initials: S
authors.lastname: Uplekar
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland. ming.zhang.1@unil.ch.|Current addresses: Department of Biochemistry, University of Lausanne, Quartier UNIL-Epalinges, Ch. des Boveresses 155, CH-1066, Epalinges, Switzerland. ming.zhang.1@unil.ch.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland. jeremie.piton@epfl.ch.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Piton
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland. stewart.cole@epfl.ch.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland. claudia.sala@epfl.ch.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sala
mesh_terms: D055028:Comparative Genomic Hybridization; D016680:Genome, Bacterial; D059014:High-Throughput Nucleotide Sequencing; D054643:INDEL Mutation; D008958:Models, Molecular; D058977:Molecular Sequence Annotation; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D012329:RNA, Bacterial / Q000235:genetics; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D054680:Ribosome Subunits, Small, Bacterial / Q000235:genetics; D017423:Sequence Analysis, RNA; D013307:Streptomycin / Q000494:pharmacology*; D059467:Transcriptome
chemical_list: D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S; D013307:Streptomycin