Peptidomimetic analogues of an Arg-Trp-x-x-Trp motif responsible for interaction of translocase MraY with bacteriophage ϕX174 lysis protein E

• Published in: Bioorganic & medicinal chemistry Vol. 52; p. 116502
• Main Authors: Kerr, Rachel V., Fairbairn, Julia A., Merritt, Andrew T., Bugg, Timothy D.H.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2021; Elsevier
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Antimicrobial peptide; Antimicrobial Peptides - chemical synthesis; Antimicrobial Peptides - chemistry; Antimicrobial Peptides - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Escherichia coli - drug effects; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Peptidomimetic; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Protein–protein interaction; Pseudomonas aeruginosa - drug effects; Science & Technology; Structure-Activity Relationship; Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors; Transferases (Other Substituted Phosphate Groups) - metabolism; translocase MraY; Viral Proteins - antagonists & inhibitors; Viral Proteins - metabolism; translocase MraY; Antibacterial; Peptidomimetic; Protein–protein interaction; Antimicrobial peptide; DESIGN; DOMAIN; Protein-protein interaction; ESCHERICHIA-COLI; ANTIMICROBIAL PEPTIDES; IDENTIFICATION; DISCOVERY; POTENT; INHIBITORS; SPECTRUM; PENTAPEPTIDE-TRANSLOCASE
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116502

[Display omitted] 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 (MIC50P. fluorescens 5 µg/mL) and Arg-Trp-decyl ester (MIC50P. fluorescens 3 µg/mL) showing enhanced antimicrobial activity. Synthesis and testing of α-helix peptidomimetic analogues for this motif revealed improved antibacterial activity (MIC50E. 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.