Contribution of amphipathicity and hydrophobicity to the antimicrobial activity and cytotoxicity of β‑hairpin peptides

Edwards, Ingrid A., Elliott, Alysha G., Kavanagh, Angela M., Zuegg, Johannes, Blaskovich, Mark A. T. and Cooper, Matthew A. (2016) Contribution of amphipathicity and hydrophobicity to the antimicrobial activity and cytotoxicity of β‑hairpin peptides. ACS Infectious Diseases, 2 6: 442-450. doi:10.1021/acsinfecdis.6b00045


Author Edwards, Ingrid A.
Elliott, Alysha G.
Kavanagh, Angela M.
Zuegg, Johannes
Blaskovich, Mark A. T.
Cooper, Matthew A.
Title Contribution of amphipathicity and hydrophobicity to the antimicrobial activity and cytotoxicity of β‑hairpin peptides
Journal name ACS Infectious Diseases   Check publisher's open access policy
ISSN 2373-8227
Publication date 2016-04-29
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acsinfecdis.6b00045
Open Access Status Not Open Access
Volume 2
Issue 6
Start page 442
End page 450
Total pages 9
Place of publication Washington DC, United States
Publisher American Chemical Society
Collection year 2017
Language eng
Formatted abstract
Bacteria have acquired extensive resistance mechanisms to protect themselves against antibiotic action. Today the bacterial membrane has become one of the “final frontiers” in the search for new compounds acting on novel targets to address the threat of multi-drug resistant (MDR) and XDR bacterial pathogens. β-Hairpin antimicrobial peptides are amphipathic, membrane-binding antibiotics that exhibit a broad range of activities against Gram-positive, Gram-negative, and fungal pathogens. However, most members of the class also possess adverse cytotoxicity and hemolytic activity that preclude their development as candidate antimicrobials. We examined peptide hydrophobicity, amphipathicity, and structure to better dissect and understand the correlation between antimicrobial activity and toxicity, membrane binding, and membrane permeability. The hydrophobicity, pI, net charge at physiological pH, and amphipathic moment for the β-hairpin antimicrobial peptides tachyplesin-1, polyphemusin-1, protegrin-1, gomesin, arenicin-3, and thanatin were determined and correlated with key antimicrobial activity and toxicity data. These included antimicrobial activity against five key bacterial pathogens and two fungi, cytotoxicity against human cell lines, and hemolytic activity in human erythrocytes. Observed antimicrobial activity trends correlated with compound amphipathicity and, to a lesser extent, with overall hydrophobicity. Antimicrobial activity increased with amphipathicity, but unfortunately so did toxicity. Of note, tachyplesin-1 was found to be 8-fold more amphipathic than gomesin. These analyses identify tachyplesin-1 as a promising scaffold for rational design and synthetic optimization toward an antibiotic candidate.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 27 May 2016, 01:02:37 EST by Susan Allen on behalf of Institute for Molecular Bioscience