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Title: Life and death : cell wall antibiotic killing of Staphylococcus aureus
Author: von und zur Mühlen, Milena Louise
ISNI:       0000 0004 8509 1422
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2019
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The bacterial cell wall is a complex structure essential for life. The primary structural component of the wall for most bacteria, including the major human pathogen Staphylococcus aureus, is peptidoglycan. As peptidoglycan is unique to bacteria its synthesis forms the target for some of the most important clinically used antibiotics. The spread of antibiotic resistance is a global healthcare challenge. Addressing this massive problem requires a multifaceted approach ranging from reducing antibiotic use, to the discovery of new antibiotic interventions and alternatives. The ß-lactam and glycopeptide groups of antibiotics that target cell wall synthesis, exemplified by methicillin and vancomycin respectively, are some of the most commonly used antibiotics to treat S. aureus infections. The molecular pathway to bacterial cell death after treatment of S. aureus with these compounds is not well understood even after decades of clinical efficacy. To elucidate the bactericidal mechanism of methicillin and vancomycin, an integrated range of approaches was taken. Characteristically, methicillin treatment initially shows a small increase in cell numbers prior to a decrease due to the action of the antibiotic, whereas vancomycin kills more slowly but without the initial increase. Structured illumination microscopy (SIM) demonstrated that both vancomycin and methicillin led to a significant cell volume increase prior to death in the absence of any peptidoglycan synthesis. Electron microscopy revealed that only with methicillin were bulbous septa apparent. Methicillin-treated cells still divided if they had a complete septum upon antibiotic addition whereas vancomycin treated cells did not. This difference was likely due to the action of peptidoglycan hydrolases at the presumptive septum. A new model of the action of antibiotics was derived from this research. In combination with other data derived during the time of my PhD, this has led to an overarching theory as to how bacteria can grow and the activity of cell wall antibiotics. Utilisation of this data provides novel avenues for the use of existing antibiotics and the development of new ones.
Supervisor: Foster, Simon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available