How do Self-Assembling Antimicrobial Lipopeptides Kill Bacteria?

Haoning Gong, Marc-antoine Sani, Xuzhi Hu, Ke Fa, Jack William Hart, Mingrui Liao, Peter Hollowell, Jessica Carter, Luke A. Clifton, Mario Campana, Peixun Li, Stephen M. King, John R. P. Webster, Armando Maestro, Shiying Zhu, Frances Separovic, Thomas A. Waigh, Hai Xu, Andrew J. Mcbain, Jian Ren Lu

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Abstract

Antimicrobial peptides are promising alternatives to traditional antibiotics. A group of self-assembling lipopeptides was formed by attaching an acyl chain to the N-terminus of α-helix-forming peptides with the sequence Cx-G(IIKK)yI-NH2 (CxGy, x = 4–12 and y = 2). CxGy self-assemble into nanofibers above their critical aggregation concentrations (CACs). With increasing x, the CACs decrease and the hydrophobic interactions increase, promoting secondary structure transitions within the nanofibers. Antimicrobial activity, determined by the minimum inhibition concentration (MIC), also decreases with increasing x, but the MICs are significantly smaller than the CACs, suggesting effective bacterial membrane-disrupting power. Unlike conventional antibiotics, both C8G2 and C12G2 can kill Staphylococcus aureus and Escherichia coli after only minutes of exposure under the concentrations studied. C12G2 nanofibers have considerably faster killing dynamics and lower cytotoxicity than their nonaggregated monomers. Antimicrobial activity of peptide aggregates has, to date, been underexploited, and it is found to be a very promising mechanism for peptide design. Detailed evidence for the molecular mechanisms involved is provided, based on superresolution fluorescence microscopy, solid-state nuclear magnetic resonance, atomic force microscopy, neutron scattering/reflectivity, circular dichroism, and Brewster angle microscopy.
Original languageEnglish
Pages (from-to)55675-55687
JournalACS applied materials & interfaces
Volume12
Issue number50
DOIs
Publication statusPublished - 1 Dec 2020

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