Chain-End Modifications and Sequence Arrangements of Antimicrobial Peptoids for Mediating Activity and Nano-Assembly
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)...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2020.00416/full |
| _version_ | 1811212825269370880 |
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| author | Abshar Hasan Abshar Hasan Varun Saxena Varun Saxena Valeria Castelletto Georgina Zimbitas Jani Seitsonen Janne Ruokolainen Lalit M. Pandey Jan Sefcik Ian W. Hamley King Hang Aaron Lau |
| author_facet | Abshar Hasan Abshar Hasan Varun Saxena Varun Saxena Valeria Castelletto Georgina Zimbitas Jani Seitsonen Janne Ruokolainen Lalit M. Pandey Jan Sefcik Ian W. Hamley King Hang Aaron Lau |
| author_sort | Abshar Hasan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T05:36:50Z |
| format | Article |
| id | doaj.art-96d36f2060344f06b3e9f6d2ec518ee5 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-12T05:36:50Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Chemistry |
| spelling | doaj.art-96d36f2060344f06b3e9f6d2ec518ee52022-12-22T03:45:50ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462020-05-01810.3389/fchem.2020.00416536818Chain-End Modifications and Sequence Arrangements of Antimicrobial Peptoids for Mediating Activity and Nano-AssemblyAbshar Hasan0Abshar Hasan1Varun Saxena2Varun Saxena3Valeria Castelletto4Georgina Zimbitas5Jani Seitsonen6Janne Ruokolainen7Lalit M. Pandey8Jan Sefcik9Ian W. Hamley10King Hang Aaron Lau11Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, United KingdomDepartment of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, IndiaDepartment of Pure and Applied Chemistry, University of Strathclyde, Glasgow, United KingdomDepartment of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, IndiaDepartment of Chemistry, University of Reading, Reading, United KingdomDepartment of Chemical and Process Engineering, University of Strathclyde, Glasgow, United KingdomNanomicroscopy Center, Aalto University, Espoo, FinlandNanomicroscopy Center, Aalto University, Espoo, FinlandDepartment of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, IndiaDepartment of Chemical and Process Engineering, University of Strathclyde, Glasgow, United KingdomDepartment of Chemistry, University of Reading, Reading, United KingdomDepartment of Pure and Applied Chemistry, University of Strathclyde, Glasgow, United KingdomPoly(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.https://www.frontiersin.org/article/10.3389/fchem.2020.00416/fullself-assemblymicellesantimicrobial peptidepeptoidsDLSCAC |
| spellingShingle | Abshar Hasan Abshar Hasan Varun Saxena Varun Saxena Valeria Castelletto Georgina Zimbitas Jani Seitsonen Janne Ruokolainen Lalit M. Pandey Jan Sefcik Ian W. Hamley King Hang Aaron Lau Chain-End Modifications and Sequence Arrangements of Antimicrobial Peptoids for Mediating Activity and Nano-Assembly Frontiers in Chemistry self-assembly micelles antimicrobial peptide peptoids DLS CAC |
| title | Chain-End Modifications and Sequence Arrangements of Antimicrobial Peptoids for Mediating Activity and Nano-Assembly |
| title_full | Chain-End Modifications and Sequence Arrangements of Antimicrobial Peptoids for Mediating Activity and Nano-Assembly |
| title_fullStr | Chain-End Modifications and Sequence Arrangements of Antimicrobial Peptoids for Mediating Activity and Nano-Assembly |
| title_full_unstemmed | Chain-End Modifications and Sequence Arrangements of Antimicrobial Peptoids for Mediating Activity and Nano-Assembly |
| title_short | Chain-End Modifications and Sequence Arrangements of Antimicrobial Peptoids for Mediating Activity and Nano-Assembly |
| title_sort | chain end modifications and sequence arrangements of antimicrobial peptoids for mediating activity and nano assembly |
| topic | self-assembly micelles antimicrobial peptide peptoids DLS CAC |
| url | https://www.frontiersin.org/article/10.3389/fchem.2020.00416/full |
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