Aggregated Amphiphilic Antimicrobial Peptides Embedded in Bacterial Membranes

Haoning Gong, Mingrui Liao, Xuzhi Hu, Ke Fa, Sorasak Phanphak, Daniela Ciumac, Peter Hollowell, Kangcheng Shen, Luke A. Clifton, Mario Campana, John R. P. Webster, Giovanna Fragneto, Thomas A. Waigh, Andrew J. Mcbain, Jian Ren Lu

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Abstract

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)3I-NH2 (G3) achieved low minimum inhibition concentrations (MICs) and effective dynamic kills against both antibiotic-resistant and -susceptible bacteria. However, a G3 derivative with weaker hydrophobicity, KI(KKII)2I-NH2 (KI), exhibited considerably lower membrane-lytic activity. In contrast, the more hydrophobic G(ILKK)3L-NH2 (GL) peptide achieved MICs similar to those observed for G3 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.
Original languageEnglish
Pages (from-to)44420-44432
JournalACS applied materials & interfaces
Volume12
Issue number40
Early online date10 Sept 2020
DOIs
Publication statusPublished - 7 Oct 2020

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