Prof Tony Maxwell

Project Leader
Biological Chemistry

Tony studies the structure and function of an essential class of enzymes, DNA topoisomerases, which break the double-stranded helix of DNA.

Tony’s research aims to reveal mechanisms of action of DNA topoisomerases such as DNA gyrase, to understand how they might be disrupted.

His research then involves the development of novel compounds which target these enzymes, identifying potential new antibiotic, herbicide and anti-plasmodial compounds. 

  • Structure and function of DNA topoisomerases
  • Understanding the mechanism of action of DNA topoisomerases
  • Targeting DNA topoisomerases for antibiotic and herbicide development

 

The lab investigates the structure and mechanism of DNA topoisomerases and associated proteins, to further our understanding of key biological processes in which they are involved, and to harness this knowledge for the development of therapeutic agents, specifically antibiotics.  This work is carried out within the MfN ISP under Theme 2: Biological Context (Objective 2.2: Small-molecule target proteins).

Topoisomerases are vitally important enzymes involved in the control of the topological state of DNA.  Their major biological functions are in DNA replication, transcription and the control of gene expression.  Topoisomerases provide fascinating systems for studying DNA-protein interactions and energy coupling in biological systems.  Their study also has clinical relevance from the standpoint of antibacterial and anti-tumour drugs.  DNA gyrase, the enzyme from bacteria that carries out DNA supercoiling, is the target for clinically-important antibiotics.

In addition to gyrase, the group are working on several related enzymes, including bacterial topoisomerase IV and the recently discovered gyrases and topo VI enzymes from plants and plasmodial species.  The work involves a wide range of methodologies including bacteriology, mutagenesis, protein engineering, plant molecular biology, enzymology, biophysical methods and X-ray crystallography.

Tony's lab are also working on insect gut bacteria as a way of exploring plant toxins to assess their usefulness as potential antibiotics.  This involves analysing the microbiome of insects feeding on certain plants to obtain evidence of toxin compounds in the plant.

Biography

Tony Maxwell, who is originally from Birmingham, gained his first degree (B.Sc., 1st Class) in Biochemistry from University College London before going on to do a Ph.D. on restriction enzyme enzymology at the University of Bristol with Steve Halford.  This was followed by a 4-year postdoc with Marty Gellert (NIH, Bethesda, USA) on DNA gyrase, where he worked on structural and mechanistic aspects of the enzyme.  In 1982 he moved back to the UK where he was awarded a ‘New Blood’ Lectureship at the University of Leicester, and stayed until 2000, becoming a Professor in 1997.  During the period 1991-1997 he held a Lister-Jenner Research Fellowship.  Work at Leicester involved continued mechanistic and structural studies on gyrase and other DNA topoisomerases, and investigations into drug-targeting aspects of these enzymes.

In 2000 he moved to the John Innes Centre, which is the largest research institute for plant and microbial sciences in Europe, to be Head of the Biological Chemistry Department.  His research interests centre around DNA topoisomerases, focussing on their structure, mechanism and interaction, with a particular emphasis on antimicrobial agents; current work also includes analysis of insect microbiomes in relation to antimicrobial resistance.

Notable recent work includes: the discovery of DNA gyrase in Arabidopsis (PNAS 2004, & JBC, 2016), structure of a fluoroquinolone resistance protein from Mycobacterium tuberculosis (Science, 2005), structures of the GyrA and GyrB proteins by small angle X-ray scattering (Structure, 2005 & 2007), development of a high-throughput assay for topoisomerases (NAR, 2006), and the crystal structure of simocyclinone bound to gyrase (Science, 2009 & JMB, 2014).  He is co-author (with Andy Bates) of the book ‘DNA topology’ (OUP, 2005).

Contact

Tel: 01603 450771
tony.maxwell@jic.ac.uk

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Recent Publications

Jeannot F., Taillier T., Despeyroux P., Renard S., Rey A., Mourez M., Poeverlein C., Khichane I., Perrin M. A., Versluys S., Stavenger R. A., Huang J., Germe T., Maxwell A., Cao S., Huseby D. L., Hughes D., Bacqué E. (2018)

Imidazopyrazinones (IPYs): Non-Quinolone Bacterial Topoisomerase Inhibitors Showing Partial Cross-Resistance with Quinolones.

Journal of Medicinal Chemistry 61 p3565-3581

Publisher’s version: 10.1021/acs.jmedchem.7b01892

Colgan A. M., Quinn H. J., Kary S. C., Mitchenall L. A., Maxwell A., Cameron A. D. S., Dorman C. J. .. (2018)

Negative supercoiling of DNA by gyrase is inhibited in Salmonella enterica serovar Typhimurium during adaptation to acid stress.

Molecular Microbiology 107 p734-746

Publisher’s version: 10.1111/mmi.13911

Germe T., Voros J., Jeannot F., Taillier T., Stavenger R. A., Bacqué E., Maxwell A., Bax B. D. (2018)

A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance.

Nucleic acids research

Publisher’s version: 10.1093/nar/gky181

Wallace M. D., Waraich N. F., Debowski A. W., Corral M. G., Maxwell T., Mylne J. S., Stubbs K. A. (2018)

Developing ciprofloxacin analogues against plant DNA gyrase: a novel herbicide mode of action.

Chemical Communications 54 p1869-1872

Publisher’s version: 10.1039/c7cc09518j

Buttner M. J., Schäfer M., Lawson D. M., Maxwell A. (2018)

Structural insights into simocyclinone as an antibiotic, effector ligand and substrate.

FEMS Microbiology Reviews 42 p100112

Publisher’s version: 10.1093/femsre/fux055

View All

Tony Maxwell

  • Lesley Mitchenall Research Assistant
  • Dr Thomas Germe Postdoctoral Scientist
  • Dr Monica Agarwal Postdoctoral Scientist
  • Dr Judit Voros Postdoctoral Scientist
  • Dr Ben Bax Postdoctoral Scientist
  • Natassja Bush Postgraduate Student
  • Sara Henderson Postgraduate Student
  • Shannon McKie Postgraduate Student
  • Nidda Waraich Postgraduate Student

Media

For media enquiries, contact the John Innes Centre communications team 01603 450962, jic.communications@jic.ac.uk

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