Stomaching X-rays: Gastric microbe attack

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  • Published: Jan 7, 2013
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Stomaching X-rays: Gastric microbe attack

Helical microbe

Structure of the proton-gated urea channel from the gastric pathogen Helicobacter pylori

An X-ray investigation has revealed a potential new way to attack the common gastric infection Helicobacter pylori, a pathogen known to cause gastritis, ulcers and significantly increase the risk of developing stomach cancer.

A new way to attack H. pylori has emerged from work carried out at the SLAC National Accelerator Laboratory in the USA using X-rays from the Stanford Synchrotron Radiation Lightsource. H. pylori infamously survives the harsh acidic environment of the stomach and is thought to infect half the world's population. It leads to health problems for hundreds of millions of people from ulcers (previously thought to be due to spicy food or stress) to stomach cancer. Nobel Prize winning work that revealed the microbe to be the underlying cause of several conditions led to a need to develop an antibiotic regimen that could eradicate it quickly when coupled with stomach-acid inhibitors.

Pathogenic protection

However, Hartmut "Hudel" Luecke of the University of California, Irvine, and colleagues, David Strugatsky, Reginald McNulty, Keith Munson, Chiung-Kuang Chen, Michael Soltis, George Sachs, hoped to learn more about how the corkscrew-shaped microbe protects itself from degradation by stomach acid. Such insights might open up the possibility of finding new drugs that target the pathogen directly without the side-effects caused by broad antibiotic use which can disrupt natural and necessary gut flora and fauna.

With this study published in the journal Nature, the team has now deciphered the three-dimensional molecular structure of one possible drug target. The team homed in on a protein channel that H. pylori uses to assimilate urea from gastric juice in the stomach and break it down using its cytoplasmic urease to release ammonia and carbon dioxide, which the microbe then exudes to neatly neutralize the hydrochloric acid of the stomach. It can neutralize entering protons and thus buffer its periplasm to a pH of just over 6 even in gastric juice that is at pH below 2. The team posited that a drug that blocks those channels would inhibit this microbial protection system and so allow the infection to be eradicated.

The team explains that solving the X-ray structure of this protein channel was not particularly easy; the protein channel is, after all, embedded in the cell membrane of the bacterium and like many other membrane proteins difficult to crystallize without destroying its native structure.

Crystallising science

"We needed to grow and screen thousands of crystals," Luecke explains. "We collected over 100 separate data sets and tried numerous structural determination techniques," added SSRL team member Mike Soltis. The final data were obtained on the brightest beamline (12-2) at SLAC. "This is the hardest structure I've ever deciphered, and I've been doing this since 1984," Luecke said. "You have to try all kinds of tricks, and these crystals fought us every step of the way. But now that we have the structure, we've reached the exciting part-the prospect of creating specific, safe and effective ways to target this pathogen and wipe it out."

"The next step is the identification of specific inhibitors of the H. pylori urea channel," Luecke told SpectroscopyNOW. "We already have several candidates with submicromolar IC50 values. Our plan is to use the crystal structure to identify and/or improve inhibitors by exploiting unique structural features of the urea channel."

Related Links

Nature 2012, online: "Structure of the proton-gated urea channel from the gastric pathogen Helicobacter pylori"

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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