title: Underlying mechanism of in vivo and in vitro activity of C-terminal-amidated thanatin against clinical isolates of extended-spectrum beta-lactamase-producing Escherichia coli.
abstract: BACKGROUND
  Infections with extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) have developed resistance to current therapies. Therefore, the underlying mechanisms of in vivo and in vitro activity of C-terminal-amidated thanatin (A-thanatin) against clinical isolates of ESBL-EC were studied in an attempt to resolve this problem.
  
  
  METHODS
  A-thanatin was synthesized to determine its minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and kill curve for ESBL-EC. The hemolytic toxicity, stability, and resistance induction of A-thanatin were determined. ESBL-EC-infected mice were used to determine the in vivo activity of A-thanatin. Scanning and transmission electron microscopy and fluorescence microscopy were used to study the underlying mechanism of A-thanatin.
  
  
  RESULTS
  A-thanatin is highly effective against ESBL-EC in vitro, with MIC values ≤4 μg/mL. It has been confirmed that A-thanatin has little hemolysis and relative high stability in plasma. Excellent in vivo therapeutic effects were also observed in a septicemic animal model, with survival rates of 50.0%, 66.7%, and 91.7% in the low-dose, middle-dose, and high-dose groups, respectively. Membrane permeabilization may be a major biological action of A-thanatin.
  
  
  CONCLUSIONS
  Because the development of multidrug resistance limits the available therapeutic options, A-thanatin may provide a novel strategy for treating ESBL-EC infection and other infections due to multidrug-resistant bacteria.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hou
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Hui
authors.initials: H
authors.lastname: Bai
authors.forename: Xiaogong
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xue
authors.forename: Yingying
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Luo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D001618:beta-Lactamases / Q000096:biosynthesis*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C098076:thanatin; D001618:beta-Lactamases