Directed chemical dimerisation enhances the antibacterial activity of the antimicrobial peptide MSI-78(4–20)

Antimicrobial resistance (AMR) is on the rise, leading to 700 000 deaths worldwide in 2020. Antimicrobial peptides (AMPs) are antibiotic agents that are active against multi-drug resistant pathogens and also have a reduced risk of AMR development. Previous studies have shown that dimerisation of the...

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Bibliographic Details
Published in:Critical studies in media communication 2023-05, Vol.76 (8), p.455
Main Authors: Li, Rong, Thomas N.G. Handley, Li, Wenyi, Neil M. O’Brien-Simpson, Mohammed Akhter Hossain, Wade, John D
Format: Article
Language:English
Subjects:
Antiinfectives and antibacterials
Antimicrobial agents
Chemical activity
Coliforms
Dimerization
Dimers
E coli
Erythrocytes
Lactate dehydrogenase
Monomers
Pathogens
Peptides
Risk management
Toxicity
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Summary:Antimicrobial resistance (AMR) is on the rise, leading to 700 000 deaths worldwide in 2020. Antimicrobial peptides (AMPs) are antibiotic agents that are active against multi-drug resistant pathogens and also have a reduced risk of AMR development. Previous studies have shown that dimerisation of the proline-rich antibacterial peptide (PrAMP) Chex1–Arg20 can enhance its antimicrobial activity while also reducing its toxicity. To determine if dimerisation via a simple disulfide bond can similarly improve other classes of AMPs, the α-helical cationic peptide MSI-78(4–20) was used as a model. The monomer alone, an S-carboxamidomethyl-capped N-terminal Cys–MSI-78(4–20) analogue and the disulfide-linked dimer were successfully synthesised and their antimicrobial activity and toxicity were determined. It was shown that dimerisation enhanced antimicrobial activity against the Gram-positive opportunistic pathogen Staphylococcus aureus ATCC 29213, the Gram-negative bacteria Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 47615. The peptides showed no significant haemolytic activity with red blood cells and only induced 50% lactate dehydrogenase (LDH) release in mammalian cells at the highest tested concentration, 15 µM. The MSI-78(4–20) dimer was less cytotoxic than the monomer and S-alkyl monomer. Together, the data support the strategy of AMP chemically directed dimerisation as a means of producing potentially more therapeutically useful antimicrobial agents.
ISSN:1529-5036
DOI:10.1071/CH23022