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    Aggregated Amphiphilic Antimicrobial Peptides Embedded in Bacterial Membranes

    Year: 2020

    Journal: ACS Appl. Mater. Interfaces, Volume 12, OCT 7, page 44420–44432

    Authors: Gong, HN; Liao, MR; Hu, XZ; Fa, K; Phanphak, S; Ciumac, D; Hollowell, P; Shen, KC; Clifton, LA; Campana, M; Webster, JRP; Fragneto, G; Waigh, TA; McBain, AJ; Lu, JR

    Organizations: University of Manchester; China Scholarship CouncilChina Scholarship Council; Syngenta; STFCUK Research & Innovation (UKRI)Science & Technology Facilities Council (STFC); Lonza; MedImmune Cambridge; ISIS Neutron Facility [RB 1720227]; ILL neutron facility; Marie Curie Fellowship ITN grant [608184]; Innovate UK, Unilever and LonzaUK Research & Innovation (UKRI)Innovate UK [KTP009043, KTP10809]; AstraZenecaAstraZeneca [BB/S018492/1]

    Keywords: antimicrobial peptides; nanostructures; nanoaggregates; peptide design; antimicrobial resistance; membranes; antibiotics; pathogens

    Molecular dynamics (MD) simulations, stochastic optical reconstruction microscopy (STORM), and neutron reflection (NR) were combined to explore how antimicrobial peptides (AMPs) can be designed to promote the formation of nanoaggregates in bacterial membranes and impose effective bactericidal actions. Changes in the hydrophobicity of the designed AMPs were found to have a strong influence on their bactericidal potency and cytotoxicity. G(IIKK)(3)I-NH2 (G(3)) achieved low minimum inhibition concentrations (MICs) and effective dynamic kills against both antibiotic-resistant and -susceptible bacteria. However, a G(3) derivative with weaker hydrophobicity, KI(KKII)(2)I-NH2 (KI), exhibited considerably lower membrane-lytic activity. In contrast, the more hydrophobic G(ILKK)(3)L-NH2 (GL) peptide achieved MICs similar to those observed for G(3) but with worsened hemolysis. Both the model membranes studied by Brewster angle microscopy, zeta potential measurements, and NR and the real bacterial membranes examined with direct STORM contained membrane-inserted peptide aggregates upon AMP exposure. These structural features were well supported by MD simulations. By revealing how AMPs self-assemble in microbial membranes, this work provides important insights into AMP mechanistic actions and allows further fine-tuning of antimicrobial potency and cytotoxicity.
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