Journal Club

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Future antibiotics: Keep bacteria from sensing each other

Alone, a single cell of Pseudomona aeruginosa—the bacteria blamed for many hospital-acquired infections—can’t cause much damage to the human body. In fact, the bacteria won’t even produce virulence factors, the compounds that make it pathogenic to humans, if it doesn’t sense neighbors. But add a few thousand other cells of P. aeruginosa, and suddenly the bacteria aren’t lone warriors; they’re a team. When they sense the presence of unique signaling molecules produced by their allies, the cells start making those virulence factors, ramping up to cause an infection.

“Bacteria evolved multicellularity,” says Princeton biologist Bonnie Bassler. “They’re so small that the only way they get any bang for their buck is by coordinating activities with each other.”

In a new PNAS paper, Bassler and her colleagues report the first ever molecule that stops P. aeruginosa from quorum sensing, that ability for cells to detect their neighbors and coordinate behavior as a group. By blocking quorum sensing, the researchers found, they can decrease the virulence of P. aeruginosa and its ability to form films of bacteria on surfaces, such as those inside the body.

Bassler already knew that bacteria relied on quorum sensing to synchronize many activities, including the production of virulence factors and the formation of so-called biofilms. And she and other scientists knew how to turn on quorum sensing, by simply adding the bacteria’s own signaling molecules to a sample, making cells think more neighbors were present. But the only way to stop bacteria from sensing their neighbors was to mutate the receptors that bound those molecules, obliterating the whole system for good.

“It was useful that we could use mutants to study the effect of having no quorum sensing,” says Bassler. “But mutants are always off, you can’t turn the system back on.”

Recently, though, Bassler’s lab found a molecule called chlorolactone that blocked one of the quorum sensing receptors in Chromobacterium violaceum, a bacteria found in water and soil. She wondered whether the chlorolactone—or similar chemicals—would also work to stop quorum sensing in the more medically important P. aeruginosa. So her group created 30 possible molecules and began testing them in the bacteria. One of them, called meta-bromo-thiolactone (mBTL), bound to a quorum sensing receptor and stopped the bacteria—even when in a group—from initiating behaviors that are synchronized through quorum sensing.

“What was surprising was that shutting down this one receptor really shuts down the whole system,” says Bassler.

With the successful results in isolated bacterial cultures, Bassler’s team began testing whether the drug would work against bacteria that were actively infecting human cells. So next, they cultured the bacteria with human lung cells. Once again, adding mBTL decreased the virulence of the bacteria.

“Now we have the luxury of having both probes that turn on quorum sensing and probes that turn off quorum sensing,” says Bassler.

The chemical isn’t immediately useful as a drug in humans, she says, but the work helps shed new light on how quorum sensing works and what receptors are most important in the process. Next, her group aims to repeat the experiments in more complex scenarios—when the cells are arranged in different ways on surfaces and have flow forces acting against them—to better mimic the environment inside the human body. They also want to know what other molecules could act against quorum sensing, and whether mBTL is effective in other species of bacteria.

“All the antibiotics that we currently have work by killing the bacteria or slowing their growth,” says Bassler. “The big question is whether there’s another way to treat bacterial infections.” Blocking quorum sensing, she says, could be how antibiotics of the future work.

Categories: Microbiology
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