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Dynamite for Bacteria

Although penicillin was discovered nearly a century ago, scientists are still learning how the drug makes bacterial cells pop like overfilled balloons.

Now, in a study of the disease-causing bacterium Streptococcus pneumoniae, researchers from Harvard Medical School have discovered a suite of molecules involved in penicillin-induced bacterial bursting.

The S. pneumoniae bacterium can colonize the respiratory tract, sinuses, and nasal cavity of healthy people without causing problems. But in people with weak immune systems, the bacteria can cause disease. Illustration by Manu5/CC BY-SA 4.0The S. pneumoniae bacterium can colonize the respiratory tract, sinuses, and nasal cavity of healthy people without causing problems. But in people with weak immune systems, the bacteria can cause disease. Illustration by Manu5/CC BY-SA 4.0

The S. pneumoniae bacterium can colonize the respiratory tract, sinuses, and nasal cavity of healthy people without causing problems. But in people with weak immune systems, the bacteria can cause disease. Illustration by Manu5/CC BY-SA 4.0

The findings, reported in eLife, set the stage for developing new antibiotics to kill bacteria that have become impervious to current drugs.

“We’re finally getting mechanistic clues that explain how penicillin and related drugs cause bacterial cells to explode,” said Thomas Bernhardt, professor of microbiology in the Blavatnik Institute at Harvard Medical School and a Howard Hughes Medical Institute Investigator.

Penicillin is part of a class of drugs called beta-lactams, the most widely used antibiotics in the world. But, through “lucky” mistakes made in their DNA, bacteria have managed to thwart these life-saving drugs, said study co-author David Rudner, professor of microbiology at HMS.

In 2015, for example, the Centers for Disease Control and Prevention reported that about 30 percent of S. pneumoniae infections were caused by drug-resistant bacteria.

One way to design new antibiotics is to untangle the cell-busting molecular chain of events initiated by current drugs.

Since 1928, when Alexander Fleming famously discovered penicillin by accident, scientists have learned that beta-lactams cause bacteria to explode under the force of water influx. The bacteria targeted by these drugs are surrounded by two barriers to the outside world: an oily inner membrane and a stiffer outer cell wall. If the cell wall is weak, water pours in causing cells to swell and burst.

Escherichia coli cells burst after treatment with ampicillin, a derivative of penicillin. Scientists have uncovered clues that these cells burst due to the action of enzymes that break down the cell wall. Image credit: Bernhardt Lab

Forty years after penicillin’s discovery, scientists discovered the molecules that the drug hinders and named them penicillin-binding proteins, which glue together cell walls’ molecular bricks. Later, they learned that stopping cell-wall construction is not enough to cause S. pneumoniae to burst. The activity of a remodeling enzyme called LytA is also required.

LytA is like a sledgehammer that breaks down parts of the cell wall. Normally, this breakage lets cells grow and divide. But if the enzyme “works overtime,” Bernhardt said, it can cause cells to disintegrate. So, he reasoned, there must be something keeping LytA’s remodeling work under control.

Josué Flores-Kim, research fellow in microbiology at HMS, started searching for the evasive culprit.

What he found involves an enzyme called TacL and a duo of molecules that control LytA’s location and, consequently, its activity.

In a series of experiments, Flores-Kim and others on the team found that TacL helps make a chain-like molecule that resides in the cell membrane. A similar molecule dwells in the cell wall. These two molecules act as competing magnets for LytA, the findings revealed. Normally, the membrane-based magnet keeps LytA stuck in the cell membrane, away from the wall. But if TacL is deleted—or degraded, as occurs with penicillin treatment—the wall-embedded magnet gets the upper hand. As a result, LytA (and its sledgehammering power) moves to the cell wall. There, unimpeded, the enzyme does major structural damage—allowing water to seep in and blow up the cell.

“The finding that TacL is required to prevent bacteria from exploding suggests it would be a good antibiotic target,” Bernhardt said. “If we can block its activity with a drug, the cells will burst.”

What’s more, because many bacteria produce similar molecular “magnets,” the team believes their results could also apply to a host of other disease-causing bacteria.

Source: HMS


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