title: The transcriptomic response of Acinetobacter baumannii to colistin and doripenem alone and in combination in an in vitro pharmacokinetics/pharmacodynamics model.
abstract: OBJECTIVE
  Colistin remains a last-line treatment for MDR Acinetobacter baumannii and combined use of colistin and carbapenems has shown synergistic effects against MDR strains. In order to understand the bacterial responses to these antibiotics, we analysed the transcriptome of A. baumannii following exposure to each.
  
  
  METHODS
  RNA sequencing was employed to determine changes in the transcriptome following treatment with colistin and doripenem, both alone and in combination, using an in vitro pharmacokinetics (PK)/pharmacodynamics model to mimic the PK of both antibiotics in patients.
  
  
  RESULTS
  After treatment with colistin (continuous infusion at 2 mg/L), >400 differentially regulated genes were identified, including many associated with outer membrane biogenesis, fatty acid metabolism and phospholipid trafficking. No genes were differentially expressed following treatment with doripenem (Cmax 25 mg/L, t1/2 1.5 h) for 15 min, but 45 genes were identified as differentially expressed after 1 h of growth under this condition. Treatment of A. baumannii with both colistin and doripenem together for 1 h resulted in >450 genes being identified as differentially expressed. More than 70% of these gene expression changes were also observed following colistin treatment alone.
  
  
  CONCLUSIONS
  These data suggest that colistin causes gross damage to the outer membrane, facilitates lipid exchange between the inner and outer membrane and alters the normal asymmetric outer membrane composition. The transcriptional response to colistin was highly similar to that observed for an LPS-deficient strain, indicating that many of the observed changes are responses to outer membrane instability resulting from LPS loss.
authors.affiliation: Department of Microbiology, Monash University, Clayton, Australia.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Henry
authors.affiliation: Department of Microbiology, Monash University, Clayton, Australia.
authors.forename: Bethany
authors.initials: B
authors.lastname: Crane
authors.affiliation: Victorian Bioinformatics Consortium, Monash University, Clayton, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Powell
authors.affiliation: Department of Microbiology, Monash University, Clayton, Australia.
authors.forename: Deanna
authors.initials: D
authors.lastname: Deveson Lucas
authors.affiliation: Department of Microbiology, Monash University, Clayton, Australia State Key Laboratory of Microbial Technology, School of Life Science, Shandong University, Jinan, 250100, Shandong, P. R. China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Microbiology, Monash University, Clayton, Australia.
authors.forename: Jesús
authors.initials: J
authors.lastname: Aranda
authors.affiliation: Victorian Bioinformatics Consortium, Monash University, Clayton, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Harrison
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.affiliation: Department of Microbiology, Monash University, Clayton, Australia Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Adler
authors.affiliation: Department of Microbiology, Monash University, Clayton, Australia Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Harper
authors.affiliation: Department of Microbiology, Monash University, Clayton, Australia john.boyce@monash.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Boyce
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015780:Carbapenems / Q000493:pharmacokinetics / Q000494:pharmacology*; D003091:Colistin / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077726:Doripenem; D020869:Gene Expression Profiling; D008962:Models, Theoretical; D017423:Sequence Analysis, RNA; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem; D003091:Colistin
keywords: carbapenems; polymyxin resistance; polymyxins