- Discovery paves the way for new drugs to fight bacterial infections
BBSRC-funded scientists working with colleagues in the UK and France have gained the first structural insights into the warfare that takes place when bacteria are starved of nutrients. Bacteria produce antimicrobial lasso peptides, which have a unique knotted structure; when they come face-to-face with receptors at the outer membranes of cells of other bacteria that cause human infections, such as E. coli or Salmonella, these peptides can hijack the receptor and kill the target bacteria.
To uncover the bacterial war tactics, scientists used structural data collected on the crystallography beamlines at Diamond Light Source, the UK's national synchrotron science facility, combined with modelling and biochemical experiments. The team brought together scientists from Imperial College London, the Muséum National d'Histoire Naturelle in Paris and the University of Oxford, and their results have just been published in Nature Chemical Biology.
Battle lines are drawn when the E. coli bacteria are starved of iron and seek it out via iron receptors on their outer membrane. These receptors are important and help bacteria to track down iron, but covert operations come into force as the lasso peptides hijack these receptors for their own purposes and kill the bacteria in the process. Ironically, such clashes between bacteria could actually prove very useful to humans in our fight against bacterial infections.
Konstantinos Beis, from the Department of Life Sciences at Imperial College London, comments: "Successfully treating infectious diseases is currently a huge challenge as bacteria are so good at shrugging off existing antibiotics by developing resistance to them. The structural studies we carried out at Diamond are very exciting as we have identified a key residue in this particular peptide that is important for the recognition of the E. coli receptor and this detailed knowledge, coupled with the fact it has a very stable lasso structure, leads us to believe the peptide could act as a platform for new drugs against bacterial infection."
There is growing interest in new approaches to tackling bacterial infections as traditional antibiotics made from purely synthetic compounds prove themselves to be not up to the job in the long term. The European Centre for Disease Preventon and Control estimates that 25,000 patients die each year from infections caused by anti microbial resistant bacteria.
Sylvie Rebuffat, from the Muséum National d'Histoire Naturelle-CNRS in Paris, adds "My team has been working on this particular peptide for over a decade now and, while these are early stage results, they provide the structural information that we have been waiting for to enable us to establish it as a front runner to aid in the design of new medicine to fight bacterial infections."
The research was funded by the Medical Research Council, the Wellcome Trust and the Biotechnology and Biological Sciences Research Council.
Notes to editors
Published in Nature Chemical online 6th April 2014 "Structural basis for hijacking siderophore receptors by antimicrobial lasso peptides", DOI: 10.1038/NCHEMBIO.1499. Indran Mathavan, Séverine Zirah, Shahid Mehmood, Hassanul G Choudhury, Christophe Goulard, Yanyan Li, Carol V Robinson, Sylvie Rebuffat & Konstantinos Beis
About Diamond Light Source
Diamond Light Source is funded by the UK Government through the Science and Technology Facilities Council (STFC), and by the Wellcome Trust.
Diamond generates extremely intense pin-point beams of synchrotron light. These are of exceptional quality, and range from X-rays to ultra-violet to infrared. Diamond's X-rays are around 10 billion times brighter than the sun.
Diamond Light Source is used by over 3,000 academic and industrial researchers across a wide range of disciplines, including structural biology, health and medicine, solid-state physics, materials & magnetism, nanoscience, electronics, earth & environmental sciences, chemistry, cultural heritage, energy and engineering. Many everyday commodities that we take for granted, from food manufacturing to consumer product, from revolutionary drugs to surgical tools, from computers to mobile phones, have all been developed or improved using synchrotron light. For more information about Diamond visit www.diamond.ac.uk
About Imperial College London
Consistently rated amongst the world's best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment - underpinned by a dynamic enterprise culture.
Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges.
In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK's first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible. Website: www.imperial.ac.uk