title: Role of the BaeSR two-component system in the regulation of Acinetobacter baumannii adeAB genes and its correlation with tigecycline susceptibility.
abstract: BACKGROUND
  Tigecycline resistance in Acinetobacter baumannii is primarily acquired through overexpression of the AdeABC efflux pump. Besides AdeRS, other two-component regulatory systems (TCSs) involving the regulation of this transporter have not been clarified.
  
  
  RESULTS
  In this study, we found that the TCS genes baeR and baeS are co-transcribed and function as stress responders under high osmotic conditions. The baeSR and adeAB genes showed increased transcription in both the laboratory-induced and clinical tigecycline-resistant strains compared with the wild-type strain. The deletion of baeR in the ATCC 17978 strain led to 67-73% and 68% reduction in adeA and adeB expression, respectively, with a resultant 2-fold decrease in the tigecycline minimal inhibition concentration (MIC). In contrast, the overexpression of baeR resulted in a doubled tigecycline MIC, with a more than 2-fold increase in adeA and adeB expression. The influence of baeR knockout on adeAB gene expression can also be observed in the laboratory-induced tigecycline-resistant strain. A time-kill assay showed that the baeR deletion mutant showed an approximate 1-log10 reduction in colony forming units (CFUs) relative to the wild-type strain when the tigecycline concentration was 0.25 μg/mL throughout the assay period. The wild-type phenotype could be restored by trans-complementation with pWH1266-kanr-baeR. Increasing the tigecycline concentration to 0.5 μg/mL produced an even more marked 4.7-log10 reduction in CFUs of the baeR deletion mutant at 8 h, while only a 2.1-log10 reduction was observed for the wild-type strain.
  
  
  CONCLUSIONS
  Taken together, these data show for the first time that the BaeSR TCS influences the tigecycline susceptibility of A. baumannii through the positive regulation of the resistance-nodulation-division efflux pump genes adeA and adeB.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Lin
authors.forename: Yun-You
authors.initials: YY
authors.lastname: Lin
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Yeh
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsin-Chu City, Taiwan. cylan@life.nthu.edu.tw.
authors.forename: Chung-Yu
authors.initials: CY
authors.lastname: Lan
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D015964:Gene Expression Regulation, Bacterial; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D009997:Osmotic Pressure; D011494:Protein Kinases / Q000378:metabolism*; D013312:Stress, Physiological; D000078304:Tigecycline; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: C492436:AdeA protein, Acinetobacter baumannii; C445684:AdeB protein, Acinetobacter baumannii; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D015534:Trans-Activators; D000078304:Tigecycline; D011494:Protein Kinases; D008911:Minocycline