The
rise in prevalence of antibiotic resistant strains of bacteria
is a very significant challenge for treating life-threatening infections
worldwide. A source of novel therapeutics that has shown great promise
is a class of biomolecules known as antimicrobial peptides. Previously,
within our laboratories, we developed a new family of water-soluble
antimicrobial polyurethanes that mimic antimicrobial peptides. Within
this current investigation, studies were carried out to gain a greater
understanding of the structure/property relationships of the polyurethanes.
This was achieved by synthesizing a variety of pendant group functionalized
polyurethanes and testing their effectiveness as an antimicrobial
by carrying out minimum inhibitory concentration testing and determining
their compatibility with blood cells. Additionally, insight into the
mode of action of the polyurethanes was obtained through experiments
using dye encapsulated phospholipids and assays of bacterial cells
that indicated the ability of the polyurethanes to penetrate and disrupt
membranes. Collectively, the results indicate that the addition of
hydrophobic, uncharged polar, and anionic moieties do not have a strong
influence on the antimicrobial activity; yet, the addition of hydrophobic
groups enhances cytoplasmic membrane disruption, a larger proportion
of cationic pendant groups promotes greater outer membrane disruption
of Gram negative bacteria, and uncharged polar groups and anionic
groups improve compatibility of the polyurethanes with mammalian cells.
The self-assembly of lipid bilayer membranes to enclose functional biomolecules, thus defining a “protocell,” was a seminal moment in the emergence of life on Earth and likely occurred at the micro-environment of the mineral-water interface. Mineral-lipid interactions are also relevant in biomedical, industrial and technological processes. Yet, no structure-activity relationships (SARs) have been identified to predict lipid self-assembly at mineral surfaces. Here we examined the influence of minerals on the self-assembly and survival of vesicles composed of single chain amphiphiles as model protocell membranes. The apparent critical vesicle concentration (CVC) increased in the presence of positively-charged nanoparticulate minerals at high loadings (mg/mL) suggesting unfavorable membrane self-assembly in such situations. Above the CVC, initial vesicle formation rates were faster in the presence of minerals. Rates were correlated with the mineral’s isoelectric point (IEP) and reactive surface area. The IEP depends on the crystal structure, chemical composition and surface hydration. Thus, membrane self-assembly showed rational dependence on fundamental mineral properties. Once formed, membrane permeability (integrity) was unaffected by minerals. Suggesting that, protocells could have survived on rock surfaces. These SARs may help predict the formation and survival of protocell membranes on early Earth and other rocky planets, and amphiphile-mineral interactions in diverse other phenomena.
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