Bacterial insomnia: NMR finds dormancy inhibitors

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  • Published: Dec 15, 2016
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Bacterial insomnia: NMR finds dormancy inhibitors

Resistance is futile

Nuclear magnetic resonance (NMR) spectroscopy and other techniques have allowed an international team to reveal compounds that inhibit the bacterial ability to become dormant. Their work shows for the first time an oxygen-sensitive toxin-antitoxin system that might lead the way to new drugs to defeat bacterial resistance.

Bacterial resistance does not simply emerge through evolutionary adaptation to antibiotics, sometimes bacteria need to become dormant in order to survive the pharmaceutical weaponry. Now, using nuclear magnetic resonance (NMR) spectroscopy in a new study, an international team has found compounds that inhibit the bacterial ability to become dormant. Their work reveals for the first time an oxygen-sensitive toxin-antitoxin system that might lead the way to new drugs to defeat bacterial resistance.

It is difficult to eradicate bacteria that form biofilms. Bacteria in these films can react to environmental signals and stresses and generate a toxin that deactivates the cells, making them dormant. As such, drugs don't work. "Antibiotics can only kill bacteria when they are actively growing and dividing," explains Thomas Wood. One particular type of bacterium that can become dormant when under stress, lives in the gastrointestinal tract. Bile, secreted by the liver and stored in the gall bladder, can kill bacteria in the GI tract. However, the presence of bile represents an environmental stress to those bacteria and they begin to express a protein that is essentially an auto-toxin that puts them to sleep. When the bile level falls as the pathogenic threat to the body appears to have subsided, the bacteria then express an anti-toxin that wakes them up by destroying the inhibitor protein. This cycle of toxin to antitoxin is essential to the survival and reproduction of the bacteria when they are exposed to a wide range of external pressures and environmental insults.

Bugs on film

Now, Wood and his team have characterized the first toxin antitoxin system in a biofilm. Writing in the journal Nature Communications, they explain how this is the first toxin-antitoxin system identified as being dependent on oxygen levels. Their characterization of the system was carried out at the molecular and atomic level by colleagues at the Biomolecular NMR Laboratory at the University of Barcelona, Spain, using Escherichia coli as the model bacterium. E. coli's antitoxin structure has within it channels that are sufficiently large to allow oxygen to pass through. The toxin in this system is Hha and the antitoxin is TomB. Most known toxin- antitoxin pairs do not rely on the presence of oxygen to function, but in this Hha-TomB system, the antitoxin must oxidize the toxin in order to wake up the bacteria.

"If we understand the toxin antitoxin systems at a molecular or atomic level, we can make better antimicrobials," explains Wood. "I would argue that the toxin antitoxin systems are fundamental to the physiology of all bacteria. We hope this will give us insight into how they survive the antibiotics."

The body's immune system can relatively easily target free-swimming bacteria with antibodies and a course of antibiotics will often dispense with them if natural immunity is insufficient to quash the infection. However, bacteria that form biofilms are much more difficult to overcome. In tuberculosis, for instance, the pathogen has as many as 88 different toxins it can generate to respond to environmental stresses, which from the bacterium's point of view, includes antibodies and antibiotics. This is one of the reasons that tuberculosis must be treated with antibiotics for many months if not years for a patient to survive this disease, according to Wood. Moreover, biofilms are involved in 80 percent of human infections and are one of the strongest contributors to the emergence and rapid spread of bacteria resistant to even the most potent of antibiotic drugs.

Cell exposure

For bacteria that go into a dormant state in order to protect themselves from antibiotics, the very process of triggering this dormancy, or rather reversing it, might be a novel target for drugs that could then wake the bacteria and then finish them off with a burst of antibiotics. The team has demonstrated that 10 percent oxygen is sufficient to wake up the bacteria, but in a biofilm, the problem becomes accessibility with only the bacteria on the edges of the film being accessible to oxygen exposure.
"The next step is to understand the molecular mechanism of Hha toxicity. Ultimately, we wish to wake persister cells so that they are responsive to antibiotics," Wood told SpectroscopyNOW.

Related Links

Nature Commun 2016, 7, 13634: "An oxygen-sensitive toxin-antitoxin system"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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