Molecular dynamics (MD) simulations, stochastic optical reconstruction microscopy (STORM) and neutron reflection (NR) are combined to explore how antimicrobial peptides (AMPs) can be designed to promote the formation of nanoaggregates into bacterial membranes and impose effective bactericidal actions. Changes in the hydrophobicity of the designed AMPs were found to have strong influence on their bactericidal potency and cytotoxicity. G(IIKK) 3 I-NH 2 (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-NH 2 (KI), exhibited considerably lower membrane-lytic activity. In contrast, the more hydrophobic G(ILKK) 3 L-NH 2 (GL) peptide achieved MICs similar to those observed for G 3 , but with worsened haemolysis. 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 their mechanistic actions and allows further fine-tuning of antimicrobial potency and cytotoxicity.
Interfacial adsorption of monoclonal antibodies (mAbs) can cause structural deformation and induce undesired aggregation and precipitation. Nonionic surfactants are often added to reduce interfacial adsorption of mAbs which may occur during manufacturing, storage, and/or administration. As mAbs are commonly manufactured into ready-to-use syringes coated with silicone oil to improve lubrication, it is important to understand how an mAb, nonionic surfactant, and silicone oil interact at the oil/water interface. In this work, we have coated a polydimethylsiloxane (PDMS) nanofilm onto an optically flat silicon substrate to facilitate the measurements of adsorption of a model mAb, COE-3, and a commercial nonionic surfactant, polysorbate 80 (PS-80), at the siliconized PDMS/water interface using spectroscopic ellipsometry and neutron reflection. Compared to the uncoated SiO 2 surface (mimicking glass), COE-3 adsorption to the PDMS surface was substantially reduced, and the adsorbed layer was characterized by the dense but thin inner layer of 16 Å and an outer diffuse layer of 20 Å, indicating structural deformation. When PS-80 was exposed to the pre-adsorbed COE-3 surface, it removed 60 wt % of COE-3 and formed a co-adsorbed layer with a similar total thickness of 36 Å. When PS-80 was injected first or as a mixture with COE-3, it completely prevented COE-3 adsorption. These findings reveal the hydrophobic nature of the PDMS surface and confirm the inhibitory role of the nonionic surfactant in preventing COE-3 adsorption at the PDMS/water interface.
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