Structural studies to inform antimicrobial drug discovery and the basis of immunity against T6 effectors

Work presented in this thesis is in two parts.<br/>Part one: The X-ray crystal structures of potential antimicrobial drug targets.<br/>The protein IspF (2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase, EC: 4.6.1.12) from two pathogens (Burkholderia cenocepacia and Plasmodium falciparum) has been investigated. IspF is an enzyme of isoprenoid-precursor biosynthesis and is considered to be a potential drug target. The results of structural and fragment-screening efforts presented here inform early stage drug discovery efforts.<br/>The structure of the PabC protein (4-amino-4-deoxychorismate lyase, EC: 4.1.3.38) from the Gram-negative pathogen Pseudomonas aeruginosa was also determined. PabC is involved in the production of para-aminobenzoic acid on the path to folate. Comparisons with previously solved PabC structures identified a spatially conserved tyrosine residue in the active site and suggest that a re-evaluation of a published mechanism is warranted.<br/>Part two: Immunity proteins in the Gram-negative Type VI secretion system.<br/>The X-ray crystal structures of the proteins Rap1a and Rap2a from Serratia marcescens, inhibitors of the peptidoglycan amidase toxins secreted by some Gram-negative bacteria employing the Type VI secretion pathway, were determined by molecular replacement and analysed.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Dundee

Year dc:date.issued

2013

Author dc:creator

• O'Rourke, Patrick

Advisor dc:contributor.advisor

• Hunter, William

• X-ray
• Crystallography
• Structural biology
• Drug discovery
• Antimicrobial
• Type VI secretion
• IspF
• PabC
• 2C-methyl-D-erythritol 2,4-cyclodiphosphate
• Para-aminobenzoic acid
• 4-amino-4-deoxychorismate lyase
• fragment screening

Language dc:language

eng

Identifier

oai:discovery.dundee.ac.uk:studenttheses/f4b1cd50-c6b3-4cbb-b313-344106bfce5c

OAI identifier oai:identifier

oai:discovery.dundee.ac.uk:studenttheses/f4b1cd50-c6b3-4cbb-b313-344106bfce5c