Difference between revisions of "Streptomyces:Research"

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===<font style="color:yellow"><b>Rebecca Goss</b></font>===
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====Key Research Interests====
====Key Research Interests====

Revision as of 06:21, 15 March 2007

Our research outline

Streptomyces @ UEA

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Gabriella Kelemen

Key Research Interests

Our 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:

  • The role of specific RNA polymerase holoenzymes controlling development and stress response
  • Global characterisation of spore maturation and germination
  • Cytoskeletal proteins
  • Chromosome organisation during hyphal growth

Matt Hutchings

Key Research Interests

In 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).

Figure 1. Classical model for a bacterial two-component signal transduction pathway.

We have been studying these signal transduction pathways in the filamentous bacterium Streptomyces coelicolor. S. coelicolor is the model organism for the genus Streptomyces, a group of bacteria that produce about 80% of commercially important antibiotics. The streptomycetes are soil bacteria and undergo a complex life cycle that includes hyphal growth and sporulation. The S. coelicolor genome encodes 164 two-component proteins, more than nearly any other bacterium. This reflects both its complex life cycle and the highly variable soil environment in which it lives. We are investigating the signal transduction systems of S. coelicolor to work out how streptomycetes sense stresses (such as nutrient starvation and antibiotic attack from competing microorganisms) that trigger antibiotic production and sporulation.

Figure 2. (A) wild type S. coelicolor, (B), a mutant which has lost the ability to sporulate, (C) a strain which overproduces the blue pigmented antibiotic actinorhodin and (D) a cross section of a colony showing the substrate mycelium (sm), aerial mycelium (am) and production of the antibiotic undecylprodigiosin, also known as “red”. Prodigiosins have recently been shown to have strong anti-cancer properties.

Richard Bowater

Key Research Interests

Having 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:

  • physiological functions of DNA ligases in bacteria
  • RNA ligases of bacteria and viruses
  • Application of novel approaches to assay the integrity of the backbone of nucleic acids
  • DNA repair pathways of Ferroplasma acidarmanus - this archaea grows at 40 °C in the most acidic environment on earth (pH <1)!
  • Relationship between DNA metabolism and genetic instability of DNA repeats

Rebecca Goss

Key Research Interests

The 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:

  • New halo-tryptophan "natural" products

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.

Figures 1, 2 & 3.

  • Generation of novel fluorinated rapamycin analogues via a directed biosynthetic strategy

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.

Figure 4.