Streptomycetes are responsible for over two-thirds of the naturally derived antibiotics in clinical use today. However, the widespread and often inappropriate use of these compounds has led to an alarming increase in bacterial strains that have become resistant to them. Thus, there is a continual need to develop new antibiotics. To this end, we are studying the biosynthesis of a class of antibiotics termed the aminocoumarins, which are natural products of Streptomycetes. There are three main compounds: novobiocin, clorobiocin and coumermycin A₁ that are synthesised by enzymes encoded in the nov, clo and cou gene clusters, respectively. They all share common structural features: a 3-amino-4,7-dihydroxycoumarin ring, an L-noviosyl sugar and an aromatic acyl component attached to the amino group of the aminocoumarin moiety. These compounds are potent inhibitors of DNA gyrase, an essential enzyme in bacteria and a validated drug target. However, they have not seen widespread clinical application on account of their low solubility, poor uptake and eukaryotic cell toxicity. Using a combination of structural and mechanistic approaches, we aim to inform the rational redesign of these compounds through the manipulation of individual enzymes in the pathways. This is an international collaboration involving Chris Walsh (Harvard, USA), Lutz Heide (Tübingen, Germany) and Rob Field (JIC). At the same time we are studying how these compounds inhibit DNA gyrase at the molecular level (in collaboration with Tony Maxwell, JIC).The figure shows the crystal structure of NovR, an enzyme involved in novobiocin biosynthesis.

 

Transcriptional regulation in Streptomyces

We have had a long-standing interest in the regulation of transcription in Streptomyces, and in the recent past worked on a sigma factor responsible for coordinating the response to redox stress (in collaboration with Mark Buttner, JIC). More recently, we have begun to study the transcriptional repressor AbsC, a novel pleiotropic regulator of antibiotic production in S. coelicolor (in collaboration with Mervyn Bibb and Richard Morris, JIC). AbsC belongs to the MarR family of ligand-responsive transcription factors. Using a multidisciplinary approach we hope to determine its cognate ligand(s) and target DNA sequences and thereby better understand its physiological role. The figure shows an electrostatic surface representation of the AbsC structure docked onto DNA.

 

Miscellaneous collaborations

• The role of protein-protein interactions in plant virus infection (with Andy Maule, JIC)
• The perception of nodulation signalling in plants at the molecular level (with Giles Oldroyd and Stephen Bornemann, JIC)
• The enzymology of sucrose and starch metabolism in plants (with Alison Smith, Kay Denyer, Rob Field and Stephen Bornemann, JIC)
• Structural biology of sulphur assimilation in plants (with Stan Kopriva, JIC)

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