multidrug resistance – Lightsources.org

Study offers new target for antibiotic resistant bacteria

2019/06/182019/06/24

As antibiotic resistance rises, the search for new antibiotic strategies has become imperative. In 2013, the Centers for Disease Control estimated that antibiotic resistant bacteria cause at least 2 million infections and 23,000 deaths a year in the U.S.; a recent report raised the likely mortality rate to 162,044.
New Cornell research on an enzyme in bacteria essential to making DNA offers a new pathway for targeting pathogens. In “Convergent Allostery in Ribonucleotide Reductase,” published June 14 in Nature Communications, researchers used the MacCHESS research stations at the Cornell High Energy Synchrotron Source (CHESS) to reveal an unexpected mechanism of activation and inactivation in the protein ribonucleotide reductase (RNR).

Understanding the “switch” that turns RNR off provides a possible means to shut off the reproduction of harmful bacteria.
RNRs take ribonucleotides, the building blocks of RNA, and convert them to deoxyribonucleotides, the building blocks of DNA. In all organisms, the regulation of RNRs involves complex mechanisms, and for good reason: These mechanisms prevent errors and dangerous mutations.

>Read more on the CHESS website

Image: William Thomas, a graduate student in the field of chemistry and chemical biology, collects data on ribonucleotide reductase.

How stained glass can help in the battle against superbugs

2019/05/302019/06/06

Ancient skills meet cutting edge technology in the battle against antibiotic resistance

Bacteria can form colonies (known as biofilms) on the surface of objects. This is a particular problem when it occurs on medical devices implanted into the body, such as catheters, prosthetic cardiac valves and intrauterine devices, as biofilms can display resistance to both antibiotics and the body’s immune response. Any incision into the body risks a surgical infection, and if a biofilm takes hold it can be difficult to eradicate. With the rise in antibiotic resistance, scientists are seeking new ways to prevent infections, and there is increasing interest in impregnate medical devices with antimicrobial substances. In work recently published in ACS Biomaterials Science & Engineering, researchers from Aston University in Birmingham, led by Dr Richard Martin, explored the antimicrobial potential of phosphate glasses doped with cobalt, and found them to be effective against Escherichia coli, Staphylococcus aureus and Candida albicans when placed in direct contact, suggesting that cobalt-doped bioactive glasses could be developed with antimicrobial properties. The technique they discovered is similar to those used to make stained glass in medieval times.

>Read more on the Diamond Light Source website

Image: Images of the copper (left) and cobalt (right) doped bioactive glasses.
Credit: Dr Richard Martin

Toward a blueprint for anti-influenza drugs

2018/12/072019/01/08

The structures provide an atomic-level blueprint from which to design more effective anti-influenza drugs that can overcome growing drug resistance.

Influenza virus infection is a perennial problem. According to the Centers for Disease Control and Prevention, the 2017-18 flu season saw high levels of emergency-department visits for influenza-like illness, high influenza-related hospitalization rates, and elevated and geographically widespread influenza activity for an extended period.

Although yearly vaccinations can reduce the number of flu infections, these vaccines are able to target only a subset of viral strains—there is, as yet, no “universal vaccine.” As a result, there is still a need for antiviral drugs to treat the illness after infection has occurred. This is especially important for groups of people who can experience serious complications from the flu, such as those with respiratory diseases or immune disorders. In recent years, however, resistance to certain classes of antiviral drugs has become a problem.

Image: Molecular dynamics simulation of a drug molecule, amantadine (cyan sticks), in the M2 proton channel. The drug’s ammonium group (blue tip) mimics hydronium, stabilizing the drug molecule in a position to block the channel.

First experiments reveal unknown structure of antibiotics killer

2018/10/022018/10/08

DESY-led international collaboration obtains first scientific results from European XFEL

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.

>Read more on the DESY website and on the European XFEL website

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

How dolphins could potentially lead to new antibiotics

2018/05/172018/05/18

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