Download The interaction of DNA gyrase with microcin B17

JOHN INNES CENTRE
Department of Biological Chemistry
NORWICH RESEARCH PARK STUDENTSHIP 2006
Novel small molecules based on the bacterial toxin microcin
B17: development of topoisomerase inhibitors with antibacterial, herbicide and anti-tumour potential
 Prof. Tony Maxwell, Biological Chemistry, John Innes Centre (Primary
Supervisor)
 Prof. Chris Pickett, School of Chemical Sciences & Pharmacy, University of
East Anglia
 Dr. Judith Richards, Microbiology, Norfolk & Norwich Hospital
 Dr. Jelena Gavrilovic, School of Biological Sciences, University of East Anglia
Project suitable for students with a background in biochemistry,
chemistry or a related discipline.
Bacterial disease presents a real challenge for the 21st century. The rise in bacterial resistance to existing
agents and the withdrawal of big pharmaceutical companies from anti-bacterial research means that the
potential for crisis in infectious diseases has increased. Against this background it is essential that
academia steps up its efforts in drug discovery, specifically identifying new lead molecules and targets for
drug design. DNA topoisomerases are essential enzymes in all cells have become important targets for
antibacterials and anti-cancer agents. DNA gyrase is a topoisomerase unique to bacteria that has become
a key target for antibiotics, such as ciprofloxacin. The related enzyme from humans, DNA topo IIα, is
the target of anti-tumour drugs such as teniposide. The identification of new molecules specific for these
two enzymes is an important goal for the development of future chemotherapeutic agents.
Microcin B17 (MccB17) is a bacterial toxin that targets gyrase; however, its large size and
insolubility mean that it is not a good candidate for therapeutics. We have begun to synthesise a series of
small molecules that mimic the inhibitory properties of MccB17. We have found that several of these
molecules target gyrase and some kill E. coli; others inhibit human topo IIα and kill human tumour cells,
and show herbicide activity). These molecules have the potential to be lead molecules for drug design.
We have the combined expertise within our 4 labs across the Norwich Research Park to take this
forward by initiating an exciting multi-disciplinary postgraduate project. This will involve taking the
initial six lead molecules we have in hand to:
 define their ability to kill a range of pathogens, including MRSA (Dr Richards, N&N)
 define their activity against a range of mammalian tumour cells (Dr Gavrilovic, BIO)
 probe their mechanism of action against a range of topoisomerases
 probe their mechanism of transport into target cells (Prof. Maxwell, JIC)
 use this information to synthesise new molecules with enhanced potency (Prof Pickett, CAP).
The output from this project will be novel series of biological molecules characterised in terms of
their inhibition of topoisomerases and their efficacy against bacteria, plants and human tumour cells.
Such a broad-ranging project will provide the student with a wide range of research skills.
Please contact Tony Maxwell ([email protected]; 01603 450771) for further information.