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