title: Genome dynamics of multidrug-resistant Acinetobacter baumannii during infection and treatment.
abstract: BACKGROUND
  Limited treatment options are available for patients infected with multidrug (MDR)- or pan-drug (PDR)-resistant bacterial pathogens, resulting in infections that can persist for weeks or months. In order to better understand transmission and evolutionary dynamics of MDR Acinetobacter baumannii (Ab) during long-term infection, we analyzed genomes from a series of isolates from individual patients at isolate-specific, patient-specific, and population levels.
  
  
  METHODS
  Whole genome analysis of longitudinal isolates (range 2-10 isolates per patient spanning 0-829 days) from 40 patients included detection of single-nucleotide variants (SNVs), insertion sequence (IS) mapping, and gene content changes.
  
  
  RESULTS
  Phylogenetic analysis revealed that a significant fraction of apparently persistent infections are in fact due to re-infection with new strains. SNVs primarily resulted in protein coding changes, and IS events primarily interrupted genes or were in an orientation such that the adjacent gene would be over-expressed. Mutations acquired during infection were over-represented in transcriptional regulators, notably pmrAB and adeRS, which can mediate resistance to the last line therapies colistin and tigecycline, respectively, as well as transporters, surface structures, and iron acquisition genes.
  
  
  CONCLUSIONS
  Most SNVs and IS events were isolate-specific indicating these mutations did not become fixed on the time scale investigated, yet over-representation of independent mutations in some genes or functional categories suggests that they are under selective pressure. Genome analysis at the population-level suggests that gene transfer including recombination also contributes to Ab evolutionary dynamics. These findings provide important insight into the transmission dynamics of Ab and the identification of patients with repeat infections has implications for infection control programs targeted to this pathogen.
authors.affiliation: The J. Craig Venter Institute, La Jolla, CA, USA.
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Wright
authors.affiliation: Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Iovleva
authors.affiliation: Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH, USA.|Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jacobs
authors.affiliation: Departments of Pharmacology, Molecular Biology and Microbiology, and the Center for Proteomics, Case Western Reserve University, Cleveland, OH, USA.|Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.affiliation: The J. Craig Venter Institute, La Jolla, CA, USA. madams@jcvi.org.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Adams
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology*; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000235:genetics*; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D019295:Computational Biology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D005798:Genes, Bacterial; D014644:Genetic Variation; D016680:Genome, Bacterial; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016254:Mutagenesis, Insertional; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide
chemical_list: D000900:Anti-Bacterial Agents