Scientists uncover bacterial war tactics

Discovery paves the way for new drugs to fight bacterial infections

“Crystal structure of the membrane siderophore receptor FhuA (blue-gold) in complex with the antibacterial lasso petide MccJ25 (magenta). Comparison of the siderophore- and MccJ25-bound structures revealed that the structurally unrealted MccJ25 can hijack the FhuA by mimicking the binding mode of the siderophore. MccJ25 is also capable of inducing a transport signal through a contact with the plug domain (gold) that allows the peptide to be internalised by the target bacteria which leads to cell death. Image credit: Konstantinos Beis, Imperial College London
“Crystal structure of the membrane siderophore receptor FhuA (blue-gold) in complex with the antibacterial lasso petide MccJ25 (magenta). Comparison of the siderophore- and MccJ25-bound structures revealed that the structurally unrealted MccJ25 can hijack the FhuA by mimicking the binding mode of the siderophore. MccJ25 is also capable of inducing a transport signal through a contact with the plug domain (gold) that allows the peptide to be internalised by the target bacteria which leads to cell death. Image credit: Konstantinos Beis, Imperial College London

Scientists from 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, 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. 
Scientist turned cowboy lassos key results in our fight against bacterial infections. Image credit: Catherine Pougault from the Muséum National d'Histoire Naturelle
Scientist turned cowboy lassos key results in our fight against bacterial infections. Image credit: Catherine Pougault from the Muséum National d'Histoire Naturelle
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 Prevention 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.
 
Published in Nature Chemical Biology 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.
 
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