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    How do Self-Assembling Antimicrobial Lipopeptides Kill Bacteria?

    Year: 2020

    Journal: ACS Appl. Mater. Interfaces, Volume 12, DEC 16, page 55675–55687

    Authors: Gong, HN; Sani, MA; Hu, XZ; Fa, K; Hart, JW; Liao, MR; Hollowell, P; Carter, J; Clifton, LA; Campana, M; Li, PX; King, SM; Webster, JRP; Maestro, A; Zhu, SY; Separovic, F; Waigh, TA; Xu, H; McBain, AJ; Lu, JR

    Organizations: University of Manchester; China Scholarship CouncilChina Scholarship Council; BBSRCUK Research & Innovation (UKRI)Biotechnology and Biological Sciences Research Council (BBSRC); Syngenta; Science and Technology Facilities CouncilUK Research & Innovation (UKRI)Science & Technology Facilities Council (STFC); Lonza; MedImmune Cambridge; Marie Curie Fellowship ITN grant under SNAL (small nano-objects for alteration of lipid bilayers) [608184]; BBSRC LINK grantUK Research & Innovation (UKRI)Biotechnology and Biological Sciences Research Council (BBSRC); AstraZenecaAstraZeneca [BB/S018492/1]

    Keywords: antimicrobial peptides; infection control; sel-assembly; membrane-lytic; membrane disruption; wound care; nanofibrils; bionanomaterials

    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 alpha-helixforming peptides with the sequence C-x-G(IIKK)(y)I-NH2 (C(x)G(y), x = 4-12 and y = 2). C(x)G(y) 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 C(8)G(2) and C(12)G(2) can kill Staphylococcus aureus and Escherichia coli after only minutes of exposure under the concentrations studied. C(12)G(2) 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.
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