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Peptidomimetic analogues of an Arg-Trp-x-x-Trp motif responsible for interaction of translocase MraY with bacteriophage phiX174 lysis protein E
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Kerr, Rachel, Fairbairn, Julia A., Merritt, Andrew T. and Bugg, Timothy D. H. (2021) Peptidomimetic analogues of an Arg-Trp-x-x-Trp motif responsible for interaction of translocase MraY with bacteriophage phiX174 lysis protein E. Bioorganic & Medicinal Chemistry, 52 . 116502. doi:10.1016/j.bmc.2021.116502 ISSN 0968-0896.
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WRAP-peptidomimetic-analogues-Arg-Trp-x-x-Trp-motif-responsible-interaction-translocase-MraY-bacteriophage-phiX174-lysis-protein-Bugg-2021.pdf - Accepted Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial No Derivatives 4.0. Download (1027Kb) | Preview |
Official URL: https://doi.org/10.1016/j.bmc.2021.116502
Abstract
Translocase MraY is the target for bacteriophage ϕX174 lysis protein E, which interacts via a protein–protein interaction mediated by Phe-288 and Glu-287 of E. coli MraY, and an Arg-Trp-x-x-Trp motif on protein E, also found in several cationic antimicrobial peptides. Analogues of Arg-Trp-octyl ester, found previously to show antimicrobial activity, were tested for antimicrobial activity, with Lys-Trp-oct (MIC50 P. fluorescens 5 µg/mL) and Arg-Trp-decyl ester (MIC50 P. fluorescens 3 µg/mL) showing enhanced antimicrobial activity. Synthesis and testing of α-helix peptidomimetic analogues for this motif revealed improved antibacterial activity (MIC50 E. coli 4–7 µg/mL) for analogues containing two aromatic substituents, mimicking the Arg-Trp-x-x-Trp motif, and MraY inhibition (IC50 140 µM) by one such peptidomimetic. Investigation of mechanism of action using the Alamar Blue membrane permeabilisation assay revealed bacteriostatic and bacteriocidal mechanisms in different members of this set of compounds, raising the possibility of more than one biological target. The observed antimicrobial activity and MraY inhibition shown by peptidomimetic compounds confirms that this site could be targeted by drug-like molecules.
| Item Type: | Journal Article | ||||||||||||
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| Subjects: | Q Science > QP Physiology Q Science > QR Microbiology R Medicine > RS Pharmacy and materia medica |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||
| Library of Congress Subject Headings (LCSH): | Bacteriophages -- Research, Protein-protein interactions, Peptide antibiotics | ||||||||||||
| Journal or Publication Title: | Bioorganic & Medicinal Chemistry | ||||||||||||
| Publisher: | Elsevier | ||||||||||||
| ISSN: | 0968-0896 | ||||||||||||
| Official Date: | 15 December 2021 | ||||||||||||
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| Volume: | 52 | ||||||||||||
| Article Number: | 116502 | ||||||||||||
| DOI: | 10.1016/j.bmc.2021.116502 | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | Published | ||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||||||
| Date of first compliant deposit: | 15 November 2021 | ||||||||||||
| Date of first compliant Open Access: | 17 November 2022 | ||||||||||||
| RIOXX Funder/Project Grant: |
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