Antimicrobial lassos offer insight into bacterial warfare

Starved bacteria use antimicrobial lasso peptides to kill other bacteria by hijacking their nutrient receptors say scientists who have gained the first structural insights into the warfare between bacteria. To uncover these bacterial war tactics, structural data collected from the crystallography beamlines at Diamond Light Source in Oxfordshire was combined with modelling and biochemical experiments. Scientists discovered that bacteria use their lasso peptides – which have a unique knotted structure – to hijack receptors on the outer membranes of cells of other bacteria that cause human infections such as E. coli and Salmonella. “The lasso peptide acts like a Trojan horse and it is internalised by the cell like a “nutrient”, but once inside, it inhibits essential cellular processes,” Dr Konstantinos Beis from Imperial College London told Laboratory News. “The lasso peptide inhibits RNA polymerase, so cells start to die because they can’t control gene expression.” The battle lines are drawn when E. coli is starved of iron which it seeks it out via iron receptors on their outer membranes. The lasso peptides hijack receptors for their own purposes, killing the bacteria in the process. These encounters could actually prove useful to humans in our fight against bacterial infections: new approaches are of increasing interested as traditional antibiotics made from purely synthetic compounds are not proving to be up to the job. “Successfully treating infectious diseases is currently a huge challenge as bacteria are so good at shrugging off existing antibiotics by developing resistance to them,” said Beis. “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. The work – which also included researchers from the University of Oxford and Muséum National d’Histoire Naturelle – has been published in Nature Chemical Biology. Structural basis for hijacking siderophore receptors by antimicrobial lasso peptides