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Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids
Published on: May 4, 2018
Highly selective end-tagged antimicrobial peptides derived from PRELP
Martin Malmsten1, Gopinath Kasetty, Mukesh Pasupuleti
1Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Plos One
|February 8, 2011
Summary
Novel antimicrobial peptides (AMPs) were designed by modifying proline-rich sequences. These peptides show potent activity against resistant bacteria like MRSA and Pseudomonas aeruginosa with low toxicity, proving effective in wound models.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Rising antibiotic resistance necessitates novel antimicrobial agents.
- Pseudomonas aeruginosa and Staphylococcus aureus are critical pathogens causing severe infections.
- Antimicrobial peptides (AMPs) offer a promising alternative to conventional antibiotics.
Purpose of the Study:
- To design and optimize novel antimicrobial peptides (AMPs) targeting Pseudomonas aeruginosa and Staphylococcus aureus.
- To enhance the potency and stability of AMPs against resistant bacterial strains.
- To evaluate the safety and efficacy of designed AMPs in preclinical models.
Main Methods:
- Peptide design through C-terminal end-tagging of proline-rich sequences with hydrophobic amino acids (W, F).
- Antimicrobial activity assessed via radial diffusion, viable count, and minimal inhibitory concentration assays.
- Toxicity evaluated using hemolysis and human epithelial cell assays; mechanistic insights from liposome and fluorescence studies.
- Protease stability tested against relevant bacterial and human proteases; efficacy confirmed in ex vivo skin infection models.
Main Results:
- Hydrophobic C-terminal tagging significantly increased antimicrobial potency against S. aureus and P. aeruginosa.
- Optimized peptides demonstrated broad-spectrum activity against clinical isolates, including multi-drug resistant strains, in human plasma and blood.
- Peptides exhibited low toxicity to mammalian cells and enhanced stability against key proteases.
- The peptide RRPRPRPRPWWWW-NH(2) showed efficacy in ex vivo skin wound models against S. aureus and P. aeruginosa.
Conclusions:
- C-terminal hydrophobic end-tagging of cationic proline-rich sequences generates potent and selective AMPs.
- Designed AMPs exhibit significant activity against multiresistant bacteria and are effective in ex vivo wound models.
- Tuning peptide toxicity and proteolytic stability is achievable by modifying tag length and composition.
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