Download Novel small molecules based on the bacterial toxin microcin B17:

Ph.D. project available October, 2006
Novel small molecules based on the bacterial toxin microcin B17:
development of topoisomerase inhibitors with anti-bacterial, herbicide and antitumour potential
Supervisors:
 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
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
and development 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
both antibacterials and anti-cancer agents (1). DNA gyrase is a topoisomerase that is unique to
bacteria and has become a key target for antibiotics, such as the quinolone ciprofloxacin. The
related enzyme from humans, DNA topo IIα, is the target of anti-tumour drugs such as amsacrine
and 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 DNA gyrase (2,3); 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 based on pyrrole, oxazole and thiazole that mimic, and in
some cases exceed, the inhibitory properties of MccB17. We have found that several of these
molecules target DNA gyrase and some will kill E. coli cells; others inhibit human topo IIα and kill
human tumour cells, and show herbicide activity (patent GB045532.9). We believe that we have
now identified an exciting and promising new series of compounds (heterocycle-containing
heptapeptides) that 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, including gyrase and topo
IIα
 probe their mechanism of transport into target cells (Prof. Maxwell, JIC)
 use this information to synthesise new molecules with enhanced potency or specificity, and
iteratively design/generate compounds with superior biological properties (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.
1.
2.
3.
Bates, A.D. and Maxwell, A. (2005) DNA topology. Oxford University Press, Oxford.
Maxwell, A. (1999) DNA gyrase as a drug target. Biochem Soc Trans, 27, 48-53.
Pierrat, O.A. and Maxwell, A. (2005) Evidence for the role of DNA strand passage in the mechanism of action
of microcin B17 on DNA gyrase. Biochemistry, 44, 4204-4215.