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    Structural Disruptions of the Outer Membranes of Gram-Negative Bacteria by Rationally Designed Amphiphilic Antimicrobial Peptides

    Year: 2021

    Journal: ACS Appl. Mater. Interfaces, Volume 13, APR 14, page 16062–16074

    Authors: Gong, Haoning; Hu, Xuzhi; Liao, Mingrui; Fa, Ke; Ciumac, Daniela; Clifton, Luke A.; Sani, Marc-Antoine; King, Stephen M.; Maestro, Armando; Separovic, Frances; Waigh, Thomas A.; Xu, Hai; McBain, Andrew J.; Lu, Jian Ren

    Organizations: NSF [DMR-0520547]; European Union's Horizon 2020 research and innovation programme under the SINE2020 project [654000]; European grant from a Marie Curie Fellowship ITN under SNAL (small nano-objects for alteration of lipid bilayers) [608184]; AstraZeneca [BB/S018492/1]; BBSRC LINK grant; Innovate UK Knowledge Transfer Partnership project; Lonza [KTP 10809]

    Keywords: antimicrobial peptides; Gram-negative bacteria; lipopolysaccharide; membrane disruption; antimicrobial resistance; infection control; small-angle neutron scattering; neutron reflectivity

    Gram-negative bacteria are covered by both an inner cytoplasmic membrane (IM) and an outer membrane (OM). Antimicrobial peptides (AMPs) must first permeate through the OM and cell wall before attacking the IM to cause cytoplasmic leakage and kill the bacteria. The bacterial OM is an asymmetric bilayer with the outer leaflet primarily composed of lipopolysaccharides (LPSs) and the inner leaflet composed of phospholipids (PLs). Two cationic alpha-helical AMPs were designed to target Gram-negative bacteria, a full peptide G(IIKK)(3)I-NH2 (G(3)), and a hydrophobic lipopeptide C-8-G(IIKK)(2)I-NH2 (C(8)G(2), with C-8 denoting the octanoyl chain). LPS dominates OM functions as the first line of defense against antibiotics, thereby reducing drug susceptibility. This work explores how the two AMPs interact with LPS through several carefully chosen OM models that facilitated measurements from solid-state nuclear magnetic resonance (ss-NMR), small-angle neutron scattering (SANS), and neutron reflectivity (NR). The results revealed that G(3) molecules bound preferably to the LPS head region and functioned as bridge molecules to reassemble the dislocated lipids into bilayer stacks. In contrast, C(8)G(2) lipopeptides could quickly penetrate into the central region of the OM to cause direct removal of some membrane lipids. Different structural disruptions implicated different antimicrobial efficacies from these AMPs. The demonstration of the structural features underlying different susceptibilities of the OM to AMPs offers a useful route for the future development of strain-specific AMPs against antimicrobial-resistant pathogens.
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