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Title: How the protein antibiotic pyocin S5 kills Pseudomonas aeruginosa
Author: Behrens, Hannah Michaela
ISNI:       0000 0004 8506 9938
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Antimicrobial resistance is a deadly threat that is on the rise globally. Failure of small molecule antibiotic drug discovery programs and an increasing understanding of the dangers of antibiotic-induced dysbiosis of the microbiome have led to interest in bacteriocins as narrow-spectrum antibiotics. Pyocin S5 (PyoS5), a protein antibiotic against Pseudomonas aeruginosa, is the most potent colicin-like bacteriocin known but its structure and molecular mechanism remain poorly understood. This thesis presents the crystal structure of PyoS5, an elongated molecule with three structured domains and an unresolved N-terminal region, which enabled the functional, biochemical and biophysical characterization of this molecule. With its central domain, PyoS5 binds to common polysaccharide antigen (CPA), a lipopolysaccharide (LPS) antigen which acts as a receptor and accumulates the antibiotic on the cell surface. This is followed by binding to the outer membrane protein FptA, a TonB-dependent transporter (TBDT), by the N-terminal domain. A chimeric protein of Escherichia coli TonB and P. aeruginosa TonB1 allowed us to reconstruct the PyoS5 import process in E. coli, an approach that revealed that FptA acts as the translocator and that TonB1 energizes the import process by directly interacting with the N-terminal region of PyoS5. This import process and the structure of PyoS5 show strong similarity with those of PyoS2, which suggests that they are common to several pyocins targeting different TBDTs and delivering different cytotoxic domains into P. aeruginosa.
Supervisor: Kleanthous, Colin Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry ; Infection, Immunology and Translational Medicine