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Title: A novel linkage between maintenance of protein translational fidelity and cell wall biosynthesis in Streptococcus pneumoniae
Author: York, Anna
ISNI:       0000 0004 9357 8089
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2019
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Streptococcus pneumoniae is responsible for a large amount of morbidity and mortality worldwide, and in addition high-level penicillin resistant strains are emerging rapidly. However, MurM is a protein involved in peptidoglycan branching, which may provide hope for the reversal of b-lactam resistance in pneumococcal infection because it is essential for high-level penicillin resistance. Streptococcus pneumoniae produces large amounts of H2O2 during aerobic metabolism, but lacks the major oxidative stress response mechanisms. Therefore it is proposed that MurM plays an additional role in maintaining translational fidelity during oxidative stress. This work firstly demonstrates that H2O2 causes a reduction in post-transfer editing of two aminoacyl-tRNA synthetases (AlaRS and ThrRS) in vitro, which may result in a decrease in protein synthesis fidelity in vivo. Preliminary experiments indicate for the first time, that iGln Lipid II(Lys) can serve as a substrate for MurM in addition to Lipid II(Lys). A range of tRNA substrates have been prepared for investigating the substrate preference of MurM towards mis-charged tRNA. In silico modelling of MurM has provided an improved structure, allowing identification of the lipid substrate binding site. Additionally, interactions of MurM with the membrane, Lipid II(Lys) substrate, and membrane phsopholipids have similarly been simulated in silico. It is hoped that a better understanding of MurM’s structure, mechanism of action, and interplay with other areas of Streptococcus pneumoniae metabolism will be important advances, which may assist development of new clinical approaches towards treatment of pneumococcal infection.
Supervisor: Not available Sponsor: Midlands Integrative Biosciences Training Partnership
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR Microbiology