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: Zheng Hou, Jun Lu, Chao Fang, Ying Zhou, Hui Bai, Xiaogong Zhang, Xiaoyan Xue, Yingying Chen, Xiaoxing Luo
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 203 Issue 2 Pg. 273-82 (Jan 15 2011) ISSN: 1537-6613 [Electronic] United States
• PMID: 21288828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Antimicrobial Cationic Peptides
• thanatin
• beta-Lactamases

Topics

• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Antimicrobial Cationic Peptides (pharmacology, therapeutic use)
• Disease Models, Animal
• Escherichia coli (drug effects, enzymology)
• Escherichia coli Infections (drug therapy, microbiology)
• Female
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Microbial Viability (drug effects)
• Sepsis (drug therapy, microbiology)
• beta-Lactamases (biosynthesis)