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

  • Patrick O'Rourke

    Student thesis: Doctoral ThesisDoctor of Philosophy


    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: 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: 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
    Original languageEnglish
    SponsorsBiotechnology and Biological Sciences Research Council
    SupervisorBill Hunter (Supervisor)


    • 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

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