Two heads better than one in new antibiotic method
3rd December 2009
An antibiotic that binds to a well-established target in a novel and unexpected way could be the inspiration for designing new, more potent antibacterial drugs.
"A completely new way to beat bacteria is an exciting find at a time when resistance to existing antibiotics is growing," said Professor Tony Maxwell from the John Innes Centre, lead author on the research published in Science. JIC is an institute of the BBSRC.
The antibiotic molecule slots into pockets in the surface of a bacterial enzyme, DNA gyrase, and inhibits its activity. Gyrase is essential for bacteria to survive and grow. However, it is not present in humans so is an ideal, and already established, target for antibiotics.
"If you can knock out this enzyme, you have a potential new drug," says Prof Maxwell.
The molecule has two heads that dock into separate pockets in DNA gyrase, and together they are 100 times more powerful than when working individually. Neither pocket has previously been exploited by antibacterial drugs that target this enzyme. Although bacteria could develop resistance to this mode of action, it might be occur less readily than with other antibiotics.
"The fact that there are two pockets means that it might require simultaneous mutations in both pockets for the bacteria to acquire full resistance to the drug, which is much less likely," explains Professor Maxwell.
"You could say that this is a case of two heads being better than one."
The antibiotic molecule, simocyclinone D8 (SD8), is a currently unexploited natural product made by soil bacteria. SD8 itself does not easily penetrate bacterial cells, but it raises the possibility of finding other molecules that fit into the binding pockets, or designing molecules that work by this mechanism but that penetrate cells more easily.
The current method of antibiotic drug discovery is to screen protein targets or bacteria against vast libraries of compounds. Any hits are investigated in more detail.
The research reported in Science is a big advance as the scientists already know in detail how the molecule works. It can now be modified, or new compounds developed, to design new drugs.
‘A crystal structure of the bifunctional antibiotic, simocyclinone D8, bound to DNA gyrase' by M Edwards (JIC), R Flatman (JIC), L Mitchenall (JIC), C Stevenson (JIC), T Le (JIC), T Clarke (University of East Anglia), A McKay (University College London), H-P Fiedler (Eberhard Karls Universität Tübingen) , M Buttner (JIC), D Lawson (JIC) and A Maxwell (JIC) Science 4 December 2009: Vol. 326. no. 5958, pp. 1415 - 1418 DOI: 10.1126/science.1179123
This research was funded through JIC's core strategic grant from the BBSRC.
Notes to editors
- The John Innes Centre, www.jic.ac.uk, is an independent, world-leading research centre in plant and microbial sciences with over 800 staff. JIC is based on Norwich Research Park and carries out high quality fundamental, strategic and applied research to understand how plants and microbes work at the molecular, cellular and genetic levels. The JIC also trains scientists and students, collaborates with many other research laboratories and communicates its science to end-users and the general public. The JIC is grant-aided by the Biotechnology and Biological Sciences Research Council.
- The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, healthcare and pharmaceutical sectors.
The Babraham Institute, Institute for Animal Health, Institute of Food Research, John Innes Centre and Rothamsted Research are Institutes of BBSRC. The Institutes conduct long-term, mission-oriented research using specialist facilities. http://www.bbsrc.ac.uk
- The School of Biological Sciences at the University of East Anglia is rated as one of the best of its kind in the UK. In the latest Research Assessment Exercise, 90 per cent of research activity was classified as internationally leading, excellent or recognised.