The amphipathic nature of many antimicrobial peptides is critical to their action against bacteria and has been well studied. It is generally understood that their cationic charge initiates binding and hydrophobicity directs insertion steps toward membrane disruption. These simple parameters have long rationalized interactions within this molecular class even for more complex alpha-helix forming peptides, where interfacial hydrophobicity affects function. Aside from a few examples (e.g. daptomycin), this class of membrane-disrupting antimicrobials are typically not selective enough for systemic delivery, but many are sufficient for topical use. This clinical difficulty likely stems from a lack of additional fundamental parameters to optimize within this antimicrobial class.<br/>Using sequence-defined oligothioetheramides (oligoTEAs), we have created isomers of the same size, shape, and amphipathicity to explore new parameters for sequence-structure-function optimization. Despite their extensive physical and solution-phase similarities, our oligoTEA isomers show approximately a 10-fold difference in potency against bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). Biophysical characterization of our oligoTEAs on supported lipid bilayers reveal distinct interactions observable by fluorescence microscopy, fluorescence recovery after photobleaching (FRAP), and surface plasmon resonance (SPR). These techniques support and describe multiple kinetic states of binding, insertion, aggregation, and aggregate extraction from the lipid membrane surface. We have characterized the flux of membrane extraction, focusing on concentration dependence and kinetics of lipid removal. Also, changes to membrane fluidity of the supported lipid bilayer contribute to specific kinetic parameters in the membrane disruption. In all, these observations and parameters have converged to create a comprehensive model that describes the multi-state process of oligoTEA-membrane disruption, outside of typically understood cationic or hydrophobic composition.

Multistate characterization of interactions of isoamphipathic oligomers with bacterial mimetic membranes

256th National Meeting (2018)

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