ASU scientists uncover tuberculosis bacterium’s 'heartbeat'
A grouping of red-colored, rod-shaped Mycobacterium tuberculosis bacteria, which cause tuberculosis in human beings. CDC photo
Tuberculosis, a disease often thought of as part of the past, is reemerging across the United States.
But Arizona State University scientists have made a discovery that could help stop it.
Researchers from the School of Life Sciences and the Biodesign Center for Bioelectronics and Biosensors have identified a molecular system inside the bacterium that causes tuberculosis, called Mycobacterium tuberculosis, which acts like the organism’s heart or lungs — essential for its survival.
The system, known as PrrAB, helps the bacterium generate energy and breathe. When the researchers used a gene-silencing tool called CRISPR interference, or CRISPRi, to turn off PrrAB, the bacteria died.
“It’s absolutely critical and essential for the life of the organism,” said Shelley Haydel, a professor in the School of Life Sciences and senior author of the study. “If your heart stopped working right now, you’d die. That's what this system is for the TB bacterium.”
The findings, published in American Chemical Society: Infectious Diseases, could help pave the way for new tuberculosis treatments.
Targeting TB’s power source
In tuberculosis bacteria, PrrAB regulates genes that control respiration and energy production. Without it, the cells cannot survive.
Postdoctoral researcher Yannik Haller, the study’s first author, compared the system to the power cord of a CD player.
“If you look at a CD player, the CD is the main medium,” Haller said. “But you need power. PrrAB is kind of like the power cord that powers the CD player. If you take that power away, nothing works.”
Because humans do not have this kind of system, drugs that target PrrAB could potentially kill the bacterium without harming human cells.
DAT-48: A compound that kills tuberculosis
The ASU team also studied an experimental compound called diarylthiazole-48, or DAT-48, that functions through PrrAB.
In the lab, DAT-48 killed several strains of M. tuberculosis, including clinical ones. It did not affect related species like Mycobacterium abscessus, suggesting the compound is selective for TB.
“DAT-48 is really exciting because we’ve tried it in multiple different drug combinations,” Haller said. “They actually work better together than by themselves, and there’s what we call synergy.”
The researchers found that combining DAT-48 with existing TB drugs, such as bedaquiline and telacebec, produced stronger results than using any of the drugs alone. This combination strategy could make treatment faster and more effective.
Haydel said the results reinforce the idea that PrrAB is a promising target for new tuberculosis drugs.
“For many years, we would say, ‘This is essential for TB to live; it’s a great drug target,’” she said. “And now, there’s evidence that it really is.”
Understanding the threat
Both scientists said the timing of this discovery is important. After years of decline, tuberculosis cases have risen in parts of the United States.
“The most recent cases in Kansas City are the largest outbreak ever recorded in the U.S.,” Haller said. “There’s about 120 confirmed cases and more than 100 people undergoing therapy. For this outbreak, there’s no direct link to travel.”
Haller said the public often underestimates how widespread tuberculosis still is.
“About 1 in 4 people around the globe have been infected with TB,” he said. “It’s a huge global problem. People don’t realize how big of an issue it actually is.”
Haydel added that although the Kansas City outbreak was not drug-resistant, multidrug-resistant TB has appeared elsewhere in the world and could become a problem in the U.S.
“Being ready and having an arsenal of new drugs for TB is important,” she said. “This research could help us prepare.”
Next steps in the lab
The researchers plan to continue studying DAT-48 and the PrrAB system. Haller said the team hopes to use artificial intelligence to improve the molecule and design better versions more quickly.
“With computation, we can predict how a compound might behave in humans and make improvements before we even test it,” he said. “The field is moving toward AI-assisted design because it allows really high-throughput screening in a short time.”
Haydel said that although the team is excited by the progress, funding remains a challenge.
“We’ve been working on this project for seven years without any direct federal funding,” she said. “We’ve pieced it together. Now we need funding support to move it forward.”
For Haydel, who has studied tuberculosis for more than three decades, the project is a milestone in her career.
“I started working on TB right out of college,” she said. “It’s one of the infectious diseases that I love studying, because it’s complex and it matters.” Haller said the ultimate goal is simple: to help ensure that tuberculosis does not regain a foothold. “TB anywhere is a problem everywhere,” he said. “We’re trying to make sure we have the tools ready before it becomes one again.”
Why this research matters
Research is the invisible hand that powers America’s progress. It unlocks discoveries and creates opportunity. It develops new technologies and new ways of doing things.
Learn more about ASU discoveries that are contributing to changing the world and making America the world’s leading economic power at researchmatters.asu.edu.
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