Membrane Activity of Biomimetic Facially Amphiphilic Antibiotics

Abstract

Membranes are a central feature of all biological systems, and their ability to control many cellular processes is critically important. As a result, a better understanding of how molecules bind to and select between biological membranes is an active area of research. Antimicrobial host defense peptides are known to be membrane-active and, in many cases, exhibit discrimination between prokaryotic and eukaryotic cells. The design of synthetic molecules that capture the biological activity of these natural peptides has been shown. In this report, the interaction between our biomimetic structures and different biological membranes is reported using both model vesicle and in vitro bacterial cell experiments. Compound 1 induces 12% leakage at 20 microg/mL against phosphatidylglycerol (PG)-phosphatidylethanolamine (PE) vesicles vs only 3% leakage at 200 microg/mL against phosphatidyl-L-serine (PS)-phosphatidylcholine (PC) vesicles. Similarly, a 40% reduction in fluorescence is measured in lipid movement experiments for PG-PE compared to 10% for PS-PC at 600 s. A 30 degrees C increase in the phase transition of stearoyl-oleoyl-phosphatidylserine is observed in the presence of 1. These results show that lipid composition is more important for selectivity than overall net charge. Additionally, the overall concentration of a given lipid is another important factor. An effort is made to connect model vesicle studies with in vitro data and naturally occurring lipid compositions.

Infectious disease: Connecting innate immunity to biocidal polymers

“…Most recently, phenylene ethynylene, 11 (m = 2), was shown to be extremely effective against a very large panel of microorganisms, including antibiotic-resistant strains, and importantly was found to be remarkably non-toxic to RBCs, fibroblasts, and liver cells [38]. Small angle X-ray scattering (SAXS) and vesicle leakage studies have thus far illustrated that lipid composition, and not just charge, is an important factor in selectivity; plus the overall concentration of a given lipid was shown to be another important factor [65]. SAXS and fluorescence microscopy experiments also indicated that this AMM induces pore formation with 3 nm holes.…”

“…In this section, we attempt to summarize the use of various analytical techniques to elucidate the interaction of antimicrobial molecules with lipids, including the scope and limitation of the each technique; we apologize for any omissions, which are likely in such a large and important field. [39,64,65,68,99,102,[126][127][128][129][130][131][132][133][134][135][136][137][138]. Many HDPs, ceropin A, magainin-2, indolicidin, defensins and their synthetic mimic oligomers and polymers are able to insert and penetrate membrane vesicles releasing fluorescence dyes such as dextran, calcein, carboxyfluorescein and other probes.…”

“…NBD) is located at the inner surface of the bilayer [65,110]. Addition of HDP causes a reduction of the fluorescence intensity due to the movement of the labeled lipid to the outer surface of the bilayer followed by irreversible quenching from sodium bisulfite present in the surrounding solutions.…”

“…This suggests that the presence of AMM almost completely hinders the phase transition from the gel to LC phase. The authors concluded that lipid composition is more important for selectivity than the overall net charge [65].…”

Synthetic Mimics of Antimicrobial Peptides—A Versatile Ring‐Opening Metathesis Polymerization Based Platform for the Synthesis of Selective Antibacterial and Cell‐Penetrating Polymers

“…These molecules still possessed the rigidity of an aromatic backbone, but had no intramolecular hydrogen bonds. [18,23,24,50,55,56] While the aromatic backbone more easily allowed an overall linear conformation, the repeat units were free to rotate around their single bonds. This allowed their functional groups to orient themselves to a facially amphiphilic conformation upon contact with the cell membrane or a similar hydrophilic-hydrophobic interface.…”