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Manganese and foods that contain it

Closing the Gate on Manganese Could Open Doors to New Drugs to Treat Pneumonia

Study determines the structure of a molecule that helps the bacteria that causes pneumonia take up manganese

by SLAC National Accelerator Laboratory
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Most of us take for granted that our kids will make it to their fifth birthday, but nearly half a million children worldwide who are infected by Streptococcus pneumoniae bacteria each year never make it that far.

Spread in droplets when we cough or sneeze, the bacteria can cause deadly pneumonia, meningitis, and sepsis, as well as inner ear infections that leave children deaf. And they’re rapidly developing resistance to antibiotic treatments.

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Now, University of Melbourne researchers and their colleagues have taken a step toward a new therapeutic strategy. Working in part at the DOE’s SLAC National Accelerator Laboratory, they determined the structure of a molecule that helps S. pneumoniae take up manganese, a mineral that’s essential to its survival. The findings could aid the design of new drugs to target the molecule and deny the bacteria its manganese supply.

“Knowing the structure is the first step to developing a drug or therapy against S. pneumoniae,” said Christopher McDevitt, a microbiologist and biochemist at the University of Melbourne and one of the study’s senior authors. “Our approach would be to block this pathway and prevent the transporter bringing manganese into the bacterium.”

How to starve a pathogen

The idea of preventing S. pneumoniae from taking up manganese emerged more than a decade ago when McDevitt and fellow Melbourne biochemist Megan Maher decided to follow up on an important clue. They knew that zinc was toxic to S. pneumoniae bacteria, and they had worked out that this was because zinc blocked the bacteria from taking up the manganese they need to survive. 

“Humans need these essential minerals, but bacteria need them too,” said Maher, also a senior author on the new study. 

Researchers subsequently identified a transporter molecule that helped bring manganese in, and Maher and McDevitt realized that if they could figure out the transporter’s structure, it might be possible to design drugs to stop it from ferrying manganese into S. pneumoniae

After six years of work the researchers finally found that structure using X-ray crystallography at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL). The research took this long because membrane proteins such as the transporter Maher and McDevitt were interested in are among the hardest to study,

The many challenges of protein crystallography

Even under the best circumstances, solving the structure of a protein such as the manganese transporter is a challenge. It can take weeks or months just to figure out how to grow enough of a protein crystal, which is required to get a good X-ray image. Once crystallized, samples are often fragile and have to be kept very cold until they’re in a synchrotron X-ray beam.

Then there’s the matter of getting the crystal to a synchrotron for study. Shipping services drop off crystal samples at SSRL in special containers that protect them and maintain them at a specific temperature. Members of SSRL’s Structural Molecular Biology group get the samples ready for examination with an X-ray beam. That way researchers can run the instrumentation remotely, gathering their data without ever setting foot inside SLAC.

But this time, a shipping delay threatened the sample—after an already-long journey from Australia, the package arrived on a weekend and was in danger of warming too much by the time Monday came around. Fortunately, SSRL staff are used to that kind of problem, and scientist Tzanko Doukov went to pick it up from a shipping facility on a Saturday and got it ready for its scheduled beamline slot the next week. “I’m very glad the experiment worked so well,” Doukov said.

Maher praised Doukov and SSRL for going out of their to way to make the experiment happen. “I’ve been accessing the facilities at SSRL on and off since 1997 and have always been enormously impressed with not only the quality of the scientific facilities made available but also the professionalism and incredible support that the staff at SSRL give the users,” Maher said. “This is an excellent example.”

Closing a gate, opening a door

Now that the scientists know the structure of S. pneumoniae’s manganese transporter, they can pursue a new path toward defeating the bacteria—at a particularly important moment. Although there is a vaccine against the infection, it is not equally effective against all strains of the bacteria, and some strains have developed resistance to current antibiotics, which usually attack the bacteria’s ability to build its cell membrane. 

Targeting the bacteria’s manganese requirement via an easily accessible protein is a new approach that could, for a time at least, circumvent growing antibiotic resistance, the researchers said. 

“It’s a really attractive therapeutic target as the protein sits on the surface of the bacterium, and our bodies don’t use this type of gateway,” McDevitt said, meaning treatments might have fewer side effects. “At a time when we are seeing rising resistance to our first- and last-line antibiotics and the emergence of ‘superbugs,’ it is important that we think of new strategies to control this deadly organism.”

- This press release was originally published on the SLAC National Accelerator Laboratory website