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Chain-end modifications and sequence arrangements of antimicrobial peptoids for mediating activity and nano-assembly

DOI: 10.3389/fchem.2020.00416 DOI Help

Authors: Abshar Hasan (University of Strathclyde; Indian Institute of Technology Guwahati) , Varun Saxena (University of Strathclyde; Indian Institute of Technology Guwahati) , Valeria Castelletto (University of Reading) , Georgina Zimbitas (University of Strathclyde) , Jani Seitsonen (Aalto University) , Janne Ruokolainen (Aalto University) , Lalit M. Pandey (Indian Institute of Technology Guwahati) , Jan Sefcik (University of Strathclyde) , Ian W. Hamley (University of Reading) , King Hang Aaron Lau (University of Strathclyde)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Frontiers In Chemistry , VOL 8

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 18523

Open Access Open Access

Abstract: Poly(N-substituted glycine) “peptoids” are an interesting class of peptidomimics that can resist proteolysis and mimic naturally found antimicrobial peptides (AMPs), which exhibit wide spectrum activity against bacteria. This work investigates the possibility of modifying peptoid AMP mimics (AMPMs) with aliphatic lipid “tails” to generate “lipopeptoids” that can assemble into micellar nanostructures, and evaluates their antimicrobial activities. Two families of AMPMs with different distributions of hydrophobic and cationic residues were employed—one with a uniform repeating amphiphilicity, the other with a surfactant-like head-to-tail amphiphilicity. To further evaluate the interplay between self-assembly and activity, the lipopeptoids were variously modified at the AMPM chain ends with a diethylene glycol (EG2) and/or a cationic group (Nlys-Nlys dipeptoid) to adjust amphiphilicity and chain flexibility. Self-assembly was investigated by critical aggregation concentration (CAC) fluorescence assays and dynamic light scattering (DLS). The structure of a key species was also verified by small-angle X-ray scattering (SAXS) and cryo-electron microscopy (cryo-EM). To screen for antibacterial properties, we measured the minimum inhibitory concentrations (MIC) against S. aureus, E. coli, and P. aeruginosa. We found that certain combinations of lipid tail and AMPM sequences exhibit increased antibacterial activity (i.e., decreased MICs). Perhaps counter-intuitively, we were particularly interested in increased MICs in combination with low CACs. Concealing antimicrobial interactions due to packing of AMPMs in nano-assemblies could pave the way to AMPMs that may be “inert” even if unintentionally released and prevent microbes from gaining resistance to the lipopeptoids. Overall, incorporation of EG2 significantly improved lipopeptoids packing while the hydrophobic tail length was found to have a major influence over the MIC. One particular sequence, which we named C15-EG2-(kss)4, exhibited a very low CAC of 34 μM (0.0075 wt.%) and a significantly increased MIC above values for the unmodified AMPM. With the sequence design trends uncovered from this study, future work will focus on discovering more species such as C15-EG2-(kss)4 and on investigating release mechanisms and the potency of the released lipopeptoids.

Journal Keywords: self-assembly; micelles; antimicrobial peptide; peptoids; DLS; CAC; MIC

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: B21-High Throughput SAXS