Streptomyces:Research
Our research outline
ResearchGabriella KelemenKey Research InterestsOur main research interest is studying bacterial development of Streptomyces coelicolor, a Gram-positive, filamentous bacterium. Unlike most bacteria that divide by binary fission, in Streptomyces coelicolor long, multigenomic filaments are formed with ocasional septa and regular branching. Cell division is completed only during sporulation when 50-100 sporulation septa are laid down synchronously in the aerial hyphae generating unigenomic spore compartments. Current Projects Include:
Matt HutchingsKey Research InterestsIn order to survive, bacteria must sense and respond to their environment. One of the main ways in which bacteria do this is via two-component signal transduction pathways. In a typical two-component system the extracellular loop of the transmembrane sensor kinase senses a specific signal, autophosphorylates and passes that phosphate group to its cognate response regulator. The activated response regulator then switches on target genes to bring about a response to the original signal (Figure 1).
Richard BowaterKey Research InterestsHaving trained as a biochemist, my research interests have broadened out to encompass methodologies that involve biophysical chemistry, microbiology and molecular biology. More recently, I have even dabbled with bioinformatics and structural biology! The research focus of my group is macromolecular interactions of bacterial DNA repair proteins and we have focused attention on DNA ligases. Our experiments are performed in vitro or in bacterial model organisms. Current Projects Include:
Rebecca GossKey Research InterestsThe group is interested in the biosynthesis of natural products and in how these biosynthetic pathways may be harnessed to generate natural products of our own design. Many natural products are of medicinal importance. We are also interested in determining the molecular mode of action of drug molecules. It is our aim to couple these two interests, manipulating biosynthetic pathways to expediently access series of otherwise synthetically intractable natural product analogues, which can be utilised in structure activity determination. Current Projects Include:
The antibiotic pacidamycin (Figure 1) (Streptomyces coeruleorubidus), the HIV-1 integrase inhibitor complestatin (Figure 2) (Streptomyces lavendulae), and the potential antitumor agent spirotryprostatin (Figure 3) (Aspergillus fumigatus) all contain a tryptophan moiety. It is envisaged that synthesising and feeding halogenated tryptophans to the producing microorganisms will produce novel halogenated analogues of these compounds, with potentially improved bioactivities and bioavailabilities.
Due to its efficacy in binding proteins FKBP12 and the rapamycin associated binding protein (FRAP), rapamycin (Figure 4) (Sirolimus) is used clinically as an immunosuppressant. Crystal structure analyses have shown that a crucial hydrogen bond exists between Gln53 of FKBP12 and the hydroxyl group on the substituted cyclohexane ring of rapamycin. Glu54 is also proximal to this moiety. Modifications to the cyclohexane ring will alter these bonding interactions and could potentially have a beneficial affect on rapamycin's immunosuppressive properties. Rapamycin is biosynthesised by Streptomyces hygroscopicus. This organism has demonstrated low substrate specificity in its selection of a starter unit, the substituted cyclohexane carboxylic acid. A range of fluorinated cyclohexanoic acids are being synthesised for incorporation studies into rapamycin. Similar studies are being performed with the polyketide antibiotic erythromycin. Crystallographic studies of novel rapamycin analogues with FKBP12 and FRAP will be undertaken. |