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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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Official URL: https://doi.org/10.1016/j.bmc.2021.116502

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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
Subjects: Q Science > QP Physiology
Q Science > QR Microbiology
R Medicine > RS Pharmacy and materia medica
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
Dates:
DateEvent
15 December 2021Published
17 November 2021Available
29 October 2021Accepted
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:
Project/Grant IDRIOXX Funder NameFunder ID
CASE studentship[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
CASE studentshipLifeArchttp://dx.doi.org/10.13039/100012357
CASE studentship[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
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