Main research areas

Ligand-responsive transcriptional control in Streptomycetes

In order to survive and compete effectively, bacteria must continuously monitor both their surroundings and their physiological status, and react appropriately. The resultant cellular responses are frequently triggered by the binding of small signaling molecules to regulatory proteins. Ligand-responsive transcription factors are particularly abundant in Streptomycetes, reflecting their complex life cycles and rich natural product profiles. We wish to understand how these transcription factors recognise and bind to the operator sequences of the genes that they regulate and how these interactions are in turn modulated allosterically by effector ligands. These studies will help to define the biological roles of these transcription factors and their positions within complex signaling networks. The figure shows the antibiotic simocyclinone bound to the transcriptional repressor SimR from Streptomyces antibioticus.

Antibiotic biosynthesis in Streptomycetes

Streptomycetes produce the majority of antibiotics used in human and veterinary medicine and agriculture, as well as anti-tumour and anti-parasitic agents, herbicides, and other pharmacologically active metabolites. Through studying the biosynthetic pathways for these antibiotics, we aim to inform the manipulation of these pathways towards the development of novel compounds with therapeutic potential. Furthermore, our structure-function analyses of key enzymes provides deep insights into their mechanisms, specificities and evolution. The figure shows the enzyme CloQ from Streptomyces roseochromogenes, which is involved in the biosynthesis of clorobiocin.

 

Molecular basis of action of antibiotics against DNA topoisomerases

Topoisomerases are validated targets for antimicrobial therapy, and thus of considerable clinical interest. We are particularly interested in the essential bacterial enzyme DNA gyrase, which is targeted by a variety of compounds, most notably the quinolones and the aminocoumarins. The structures of DNA gyrase in complex with these antibiotics provide molecular level understanding of how these compounds work and how resistance may develop against them. This information may help in the design of novel compounds that may also be effective inhibitors of this enzyme. The figure shows the antibiotic simocyclinone (red) bound to E. coli DNA gyrase A.

 

 

The structural enzymology of carbohydrate active enzymes

We are studying a variety of carbohydrate active enzymes from both plant and microbial sources. Through analysing their structures and mechanisms, we propose to develop them as chemical tools, to exploit them as antibacterial targets, and to better understand carbon metabolism in plants and microbes. The figure shows barley β-amylase with an inhibitor bound in the active site.