title: Evolution of extensively drug-resistant Mycobacterium tuberculosis from a susceptible ancestor in a single patient.
abstract: BACKGROUND
  Mycobacterium tuberculosis is characterized by a low mutation rate and a lack of genetic recombination. Yet, the rise of extensively resistant strains paints a picture of a microbe with an impressive adaptive potential. Here we describe the first documented case of extensively drug-resistant tuberculosis evolved from a susceptible ancestor within a single patient.
  
  
  RESULTS
  Genome sequences of nine serial M. tuberculosis isolates from the same patient uncovered a dramatic turnover of competing lineages driven by the emergence, and subsequent fixation or loss of single nucleotide polymorphisms. For most drugs, resistance arose through independent emergence of mutations in more than one clone, of which only one ultimately prevailed as the clone carrying it expanded, displacing the other clones in the process. The vast majority of mutations identified over 3.5 years were either involved in drug resistance or hitchhiking in the genetic background of these. Additionally, RNA-sequencing of isolates grown in the absence of drug challenge revealed that the efflux-associated iniBAC operon was up-regulated over time, whereas down-regulated genes include those involved in mycolic acid synthesis.
  
  
  CONCLUSIONS
  We observed both rapid acquisitions of resistance to antimicrobial compounds mediated by individual mutations as well as a gradual increase in fitness in the presence of antibiotics, likely driven by stable gene expression reprogramming. The rapid turnover of resistance mutations and hitchhiking neutral mutations has major implications for inferring tuberculosis transmission events in situations where drug resistance evolves within transmission chains.
authors.forename: Vegard
authors.initials: V
authors.lastname: Eldholm
authors.forename: Gunnstein
authors.initials: G
authors.lastname: Norheim
authors.forename: Bent
authors.initials: B
authors.lastname: von der Lippe
authors.forename: Wibeke
authors.initials: W
authors.lastname: Kinander
authors.forename: Ulf R
authors.initials: UR
authors.lastname: Dahle
authors.forename: Dominique A
authors.initials: DA
authors.lastname: Caugant
authors.forename: Turid
authors.initials: T
authors.lastname: Mannsåker
authors.forename: Anne Torunn
authors.initials: AT
authors.lastname: Mengshoel
authors.forename: Anne Ma
authors.initials: AM
authors.lastname: Dyrhol-Riise
authors.forename: Francois
authors.initials: F
authors.lastname: Balloux
mesh_terms: D000890:Anti-Infective Agents / Q000627:therapeutic use; D019143:Evolution, Molecular; D054908:Extensively Drug-Resistant Tuberculosis / Q000235:genetics* / Q000382:microbiology; D016680:Genome, Bacterial; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000472:pathogenicity; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide
chemical_list: D000890:Anti-Infective Agents