Ancient skills meet cutting edge technology in the battle against antibiotic resistance
Credit: Dr Richard Martin
An international collaboration led by DESY and consisting of over 120 researchers has announced the results of the first scientific experiments at Europe’s new X-ray laser European XFEL. The pioneering work not only demonstrates that the new research facility can speed up experiments by more than an order of magnitude, it also reveals a previously unknown structure of an enzyme responsible for antibiotics resistance. “The groundbreaking work of the first team to use the European XFEL has paved the way for all users of the facility who greatly benefit from these pioneering experiments,” emphasises European XFEL managing director Robert Feidenhans’l. “We are very pleased – these results show that the facility works even better than we had expected and is ready to deliver new scientific breakthroughs.” The scientists present their results, including the first new protein structure solved at the European XFEL, in the journal Nature Communications.
“Being at a totally new class of facility we had to master many challenges that nobody had tackled before,” says DESY scientist Anton Barty from the Center for Free-Electron Laser Science (CFEL), who led the team of about 125 researchers involved in the first experiments that were open to the whole scientific community. “I compare it to the maiden flight of a novel aircraft: All calculations and assembly completed, everything says it will work, but not until you try it do you know whether it actually flies.”
The 3.4 kilometres long European XFEL is designed to deliver X-ray flashes every 0.000 000 220 seconds (220 nanoseconds). To unravel the three-dimensional structure of a biomolecule, such as an enzyme, the pulses are used to obtain flash X-ray exposures of tiny crystals grown from that biomolecule. Each exposure gives rise to a characteristic diffraction pattern on the detector. If enough such patterns are recorded from all sides of a crystal, the spatial structure of the biomolecule can be calculated. The structure of a biomolecule can reveal much about how it works.
Image: Artist’s impression of the experiment: When the ultra-bright X-ray flashes (violet) hit the enzyme crystals in the water jet (blue), the recorded diffraction data allow to reconstruct the spatial structure of the enzyme (right).
Credit: DESY/Lucid Berlin
The eight structural biology beamlines at the ALS have now collectively deposited over 7000 proteins into the Protein Data Bank (PDB), a worldwide, open-access repository of protein structures. The 7000th ALS protein structure (entry no. 6C7C) is an enzyme from Mycobacterium ulcerans (strain Agy99), solved with data from Beamline 5.0.2. This bacterium produces a toxin that eats away at skin tissue, causing what’s known as Buruli ulcers (Google at your own risk!). The bacterium is antibiotic-resistant, and treatment involves the surgical removal of infected tissues, including amputation.
The enzyme structure was solved by a group from the Seattle Structural Genomics Center for Infectious Disease (SSGID), whose mission is to obtain crystal structures of potential drug targets on the priority pathogen list of the National Institute of Allergy and Infectious Diseases (NIAID). As of May 2018, SSGCID has deposited 1090 structures in the PDB, with data for more than a quarter of those collected at ALS beamlines.
Image: PDB 6C7C: Enoyl-CoA hydratase, an enzyme from M. ulcerans (strain Agy99).
The world is currently living through a multidrug resistance problem, where antibiotics that traditionally work are not effective anymore. A European team of scientists at the University of Hamburg (Germany), University of Munich (Germany), University of Bordeaux (France), University of Trieste (Italy) and University of London (UK) have studied how some peptides in dolphins target bacterial ribosomes and hence, could provide clues about potential new antibiotics.
Proline-rich antimicrobial peptides (PrAMPs) are antibacterial components of the immune systems of animals such as honey bees, cows and, as this study proves, bottlenose dolphins. These peptides are a first response for the killing of bacteria. In humans, antimicrobial peptides (AMPs) mainly kill bacteria by disrupting the bacterial cell membrane, but so far no evidence of PrAMPs has been found. PrAMPs have a different mechanism of action to AMPs: they pass through the membrane of the cell without perturbing it and bind to ribosomes to inhibit protein synthesis.
The European team have been studying the mechanism of action of bacteria killing peptides in animals: “We want to compare PrAMPs from different organisms to mechanistically understand how these peptides inhibit bacteria”, Daniel Wilson explains.
Illustration showing the mechanism of Tur1A. (entire image: here)
Credits: D. Wilson