Aggregated Amphiphilic Antimicrobial Peptides Embedded in Bacterial Membranes.
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.
['Gong|Haoning|H|http://orcid.org/0000-0003-1590-2042', 'Liao|Mingrui|M|', 'Hu|Xuzhi|X|http://orcid.org/0000-0002-9246-7040', 'Fa|Ke|K|', 'Phanphak|Sorasak|S|', 'Ciumac|Daniela|D|', 'Hollowell|Peter|P|', 'Shen|Kangcheng|K|', 'Clifton|Luke A|LA|http://orcid.org/0000-0001-8754-362X', 'Campana|Mario|M|', 'Webster|John R P|JRP|', 'Fragneto|Giovanna|G|', 'Waigh|Thomas A|TA|http://orcid.org/0000-0002-7084-559X', 'McBain|Andrew J|AJ|', 'Lu|Jian Ren|JR|http://orcid.org/0000-0001-5648-3564']
D023181:Antimicrobial Cationic Peptides D001672:Biocompatible Materials D004926:Escherichia coli D008826:Microbial Sensitivity Tests D056004:Molecular Dynamics Simulation D010316:Particle Size D066329:Protein Aggregates D013211:Staphylococcus aureus D013499:Surface Properties D013501:Surface-Active Agents
antimicrobial peptides membranes nanoaggregates antibiotics antimicrobial resistance nanostructures pathogens peptide design