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

  • Patrick O'Rourke

    Student thesis: Doctoral ThesisDoctor of Philosophy

    Abstract

    Work presented in this thesis is in two parts.
    Part one: The X-ray crystal structures of potential antimicrobial drug targets.
    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.
    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.
    Part two: Immunity proteins in the Gram-negative Type VI secretion system.
    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.
    Date of Award2013
    LanguageEnglish
    Awarding Institution
    • University of Dundee
    Add any sponsors of the thesis researchBiotechnology and Biological Sciences Research Council
    SupervisorBill Hunter (Supervisor)

    Keywords

    • 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

    Cite this

    Structural studies to inform antimicrobial drug discovery and the basis of immunity against T6 effectors
    O'Rourke, P. (Author). 2013

    Student thesis: Doctoral ThesisDoctor of Philosophy