Directed chemical dimerisation enhances the antibacterial activity of the antimicrobial peptide MSI-78(4–20)
Rong Li A B # , Thomas N.G. Handley A # , Wenyi Li
C * , Neil M. O’Brien-Simpson D , Mohammed Akhter Hossain A E and John D. Wade A E *
+ Author Affiliations
- Author Affiliations
A Florey Institute of Neuroscience and Mental Health, University of Melbourne, Vic. 3010, Australia.
B Department of Biochemistry and Pharmacology, University of Melbourne, Vic. 3010, Australia.
C Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic. 3086, Australia.
D ATCV (Antimicrobial and Cancer Therapeutics and Vaccines) Research Group, Division of Basic and Clinical Oral Sciences, The Melbourne Dental School, Royal Dental Hospital, University of Melbourne, Carlton, Vic. 3053, Australia.
E School of Chemistry, University of Melbourne, Vic. 3010, Australia.
* Correspondence to: wenyi.li@latrobe.edu.au, john.wade@florey.edu.au
# These authors contributed equally to this paper
Handling Editor: Mibel Aguilar
Australian Journal of Chemistry 76(8) 455-464 https://doi.org/10.1071/CH23022
Submitted: 31 January 2023 Accepted: 20 March 2023 Published: 31 May 2023
© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)
Abstract
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.
Keywords: antimicrobial peptide, antimicrobial resistance, chemical modification, dimer, disulfide dimerisation, infections, membrane active, solid-phase peptide synthesis.
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