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Investigating the Mur ligases of Streptococcus agalactiae for the development of inhibitory fragments
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Steventon, Rebecca Jane (2022) Investigating the Mur ligases of Streptococcus agalactiae for the development of inhibitory fragments. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3909649
Abstract
Streptococcus agalactiae is the leading cause of early onset neonatal sepsis, and with antibacterial resistance within S. agalactiae increasing, it is imperative that new antibacterial drugs are identified. Proteins involved in peptidoglycan formation are an attractive target for the development of novel antibacterial drugs. The Mur ligases form part of the cytosolic stages of peptidoglycan formation, and are responsible for the stepwise addition of amino acids that constructs the peptide component of the peptidoglycan. Due to their similar catalytic mechanism and three domain structure, the Mur ligases are a promising target for the development of new antibacterial compounds.
This project has focused on identifying multi-targeting inhibitory fragments that are able to target MurD and MurE from S. agalactiae. To achieve this, biochemical assays have been developed and optimized for high throughput screening of competitive inhibitory fragments targeted towards the Mur ligases. A targeted fragment screen was then developed using in silico screening to allow the repurposing of existing protein kinase inhibitors to target the ATP-binding site of the Mur ligases. Screening of potential inhibitory fragments was carried out, allowing the identification of multi-targeting inhibitory fragments. Previous studies have suggested that there may be complex formation amongst the Mur ligases. The ability of MurD and MurE from S. agalactiae to form a binary complex was investigated using a range of cloning and expressing systems, and biophysical techniques including Microscale Thermophoresis before possible structural arrangements were predicted using computational techniques.
It is anticipated that the multi-targeting inhibitors identified via the optimized assays within this work, alongside our better understanding of complex formation amongst the Mur ligases, may be used for the development of effective Mur ligases inhibitors in the future and new potential therapeutic approaches to the treatment of bacterial infection.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology Q Science > QR Microbiology R Medicine > RC Internal medicine R Medicine > RJ Pediatrics |
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Library of Congress Subject Headings (LCSH): | Streptococcus agalactiae, Septicemia, Neonatal infections, Peptidoglycans, Ligases | ||||
Official Date: | November 2022 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | School of Life Sciences | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Dowson, Christopher G. ; Crow, Allister | ||||
Format of File: | |||||
Extent: | 261 pages : colour illustrations | ||||
Language: | eng |
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