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Efficacy of OH-CATH30 and its analogs against drug-resistant bacteria in vitro and in mouse models.

Abstract
Antimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacy in vivo hamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activity in vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteria in vitro and in vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 μg/ml against drug-resistant clinical isolates of several pathogenic species, including Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killed E. coli quickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD(50)) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistant E. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drug-resistant bacteria.
AuthorsSheng-An Li, Wen-Hui Lee, Yun Zhang
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 6 Pg. 3309-17 (Jun 2012) ISSN: 1098-6596 [Electronic] United States
PMID22491685 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimicrobial Cationic Peptides
  • Cathelicidins
Topics
  • Animals
  • Antimicrobial Cationic Peptides (chemical synthesis, chemistry, pharmacology, therapeutic use)
  • Bacterial Infections (drug therapy)
  • Cells, Cultured
  • Drug Resistance, Bacterial
  • Escherichia coli (drug effects)
  • Hemolysis
  • Humans
  • Male
  • Methicillin-Resistant Staphylococcus aureus (drug effects)
  • Mice
  • Microbial Sensitivity Tests
  • Pseudomonas aeruginosa (drug effects)
  • Cathelicidins

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