Antibacterial isoamphipathic oligomers highlight the importance of multimeric lipid aggregation for antibacterial potency

Joseph S Brown,Joseph F Hassler,Dana N Thornlow,Zeinab J Mohamed,Christopher A Alabi,Susan Daniel,Vincent P Rigoglioso,Christine M Artim

doi:10.1038/s42003-018-0230-4

Joseph S Brown, Joseph F Hassler + Show 6 more

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https://doi.org/10.1038/s42003-018-0230-4

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Journal: Communications Biology	Publication Date: Dec 1, 2018
Citations: 19	License type: open-access

Affiliation: Cornell University

Abstract

Cationic charge and hydrophobicity have long been understood to drive the potency and selectivity of antimicrobial peptides (AMPs). However, these properties alone struggle to guide broad success in vivo, where AMPs must differentiate bacterial and mammalian cells, while avoiding complex barriers. New parameters describing the biophysical processes of membrane disruption could provide new opportunities for antimicrobial optimization. In this work, we utilize oligothioetheramides (oligoTEAs) to explore the membrane-targeting mechanism of oligomers, which have the same cationic charge and hydrophobicity, yet show a unique ~ 10-fold difference in antibacterial potency. Solution-phase characterization reveals little difference in structure and dynamics. However, fluorescence microscopy of oligomer-treated Staphylococcus aureus mimetic membranes shows multimeric lipid aggregation that correlates with biological activity and helps establish a framework for the kinetic mechanism of action. Surface plasmon resonance supports the kinetic framework and supports lipid aggregation as a driver of antimicrobial function.

Highlights

Cationic charge and hydrophobicity have long been understood to drive the potency and selectivity of antimicrobial peptides (AMPs)
Relationships observed between chemical and physical properties with activity corroborate conclusions made across multiple molecular classes: a threshold of cationic charge is required for activity and hydrophobicity increases potency while increasing toxicity
This work has focused on the development of new experimental parameters for membrane-targeting antimicrobials, outside of the known properties of cationic charge and hydrophobicity

Summary

Introduction

Cationic charge and hydrophobicity have long been understood to drive the potency and selectivity of antimicrobial peptides (AMPs). To control activity and selectivity, AMPs and AMP mimetics have focused on tuning the nature, quantity, and spatial positioning of cationic charge and hydrophobicity[4,6,10,13] This optimization generally holds, even within structured macromolecules containing α-helices, where these fundamental properties lead to interfacial amphipathicity[25,26,27]. Toward understanding new parameters for AMP optimization and development, we have explored a unique pair of sequencedefined oligoTEA constitutional isomers of the same length, cationic charge, hydrophobicity, and amphipathicity[23] These antibacterial oligoTEAs (AOTs) have the same physical and chemical properties that typically guide optimization of membranedisrupting antimicrobials, but have displayed a unique differential in potency and toxicity of nearly tenfold. We are able to present new parameters that can enable further development of membranedisrupting antibacterial agents beyond typical physicochemical parameters of cationic charge and hydrophobicity

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