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Arg-Trp peptidomimetics as inhibitors of the translocase MraY-E protein interaction site
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Kerr, Rachel (2020) Arg-Trp peptidomimetics as inhibitors of the translocase MraY-E protein interaction site. PhD thesis, University of Warwick.
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WRAP_Theses_Kerr_2020.pdf - Submitted Version - Requires a PDF viewer. Download (8Mb) | Preview |
Official URL: http://webcat.warwick.ac.uk/record=b3491581~S15
Abstract
The cell wall biosynthesis pathway is made up of a number of steps which can be targeted by a number of antimicrobial natural product inhibitors. These can be utilised in medicine for the treatment of bacterial infection. One of these steps is catalysed by the membrane protein, Phoshpo-MurNAc-pentapeptide translocase, also known as MraY. Although MraY is the target of a number of known natural products there has been little success in developing inhibitors to be used clinically.
MraY is the site of action of bacteriophage ФX174 which produces lysis protein E. The RWxxW sequence of E protein is thought to be responsible an interaction between it and the ninth transmembrane helix (TM9) of MraY. Previous work showed that MraY could be inhibited by pentapeptides containing this motif. A dipeptide, NH2- Arg-Trp-octyl ester which was also based on this motif showed antimicrobial activity, but no inhibition of MraY.
This project aimed to synthesise molecules which were able to exhibit antimicrobial activity and inhibit MraY. A series of dipeptides were synthesised based on RWoct. The side chains of the amino acids were changed for other cationic and aromatic residues. The length of the octyl chain was altered. The series of dipeptides was then tested using a MIC50 determination assay and the inhibition by the dipeptides was assessed. All of the peptides showed antimicrobial activity, but none showed inhibition of MraY. Four of the most promising dipeptides were selected to be tested against the ESKAPE pathogens, and this showed some promising activity against these clinically relevant strains.
In order to see inhibition and improve the MIC50 a series of peptidomimetics were synthesised. The first series were based on a benzamide backbone. These would allow the installation of a second tryptophan residue, incorporating the entire RWxxW motif. The antimicrobial activity was maintained but still no inhibition of MraY was seen. The second series of peptidomimetics utilised a cyclic triazinedione backbone. This provided a more rigid framework and again antimicrobial activity was seen. The ESKAPE pathogen data from this second series of peptidomimetics was an improvement on that seen for the previous groups of compounds.The data obtained indicated that the compounds synthesised are working via several undetermined mechanisms which differ between compounds in the same series.
| Item Type: | Thesis (PhD) | ||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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| Library of Congress Subject Headings (LCSH): | Membrane proteins, Peptides -- Synthesis, Biomimetics, Bacterial diseases -- Treatment | ||||
| Official Date: | March 2020 | ||||
| Dates: |
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| Institution: | University of Warwick | ||||
| Theses Department: | Department of Chemistry | ||||
| Thesis Type: | PhD | ||||
| Publication Status: | Unpublished | ||||
| Supervisor(s)/Advisor: | Bugg, Tim | ||||
| Format of File: | |||||
| Extent: | xvii, 292 leaves : illustrations (some colour) | ||||
| Language: | eng |
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