PHILADELPHIA – To stop the bacteria that cause disease, medicine’s chief approach has been to go on the attack: using antibiotics that smother a microbe’s critical enzymes, foul up its genetic instructions or disrupt the formation of its cell wall.

But bacteria are shifty, and they eventually develop ways to sidestep these assaults.

On Thursday, Princeton University scientists reported progress with a less hostile approach, one they hope will someday yield an entirely new class of drugs: simply “talking” to bacteria in their own language.

In the journal Nature, the researchers said they had identified a chemical signal emitted by the bacteria that cause cholera – an age-old killer that remains a threat in developing countries. The scientists were then able to reproduce the signal in the lab, thereby stopping Vibrio cholerae from growing hair-like protrusions that it uses to latch on to the intestines.

“It’s a huge discovery,” said Helen E. Blackwell, an assistant professor of chemistry at the University of Wisconsin, Madison, who was not part of the paper.

The research is part of an emerging field called quorum sensing – literally, the study of how bacteria sense when they’ve multiplied enough to reach a critical mass, or quorum.

Individually, bacteria emit small amounts of these chemical communicators, called autoinducers, so the message isn’t “loud” enough for them to “hear.” When there are enough bacteria, and a given chemical reaches a high enough concentration, it triggers the bacteria to take some sort of collective action – say, releasing a toxin.

Drugs that manipulate these communication pathways are perhaps a decade away, but the approach is seen as promising.

– and potentially less susceptible to the thorny problem of drug resistance, Bassler said.

When a traditional antibiotic kills bacteria, typically some bugs are genetically resistant to the medicine and are then free to multiply. With time and the overuse of antibiotics, some of these drug-resistant bacteria have become serious health problems – especially in hospital settings.

Drugs based on quorum-sensing would not attack bacteria but merely exploit their natural modes of communication, so there might be less selective pressure on the microbes to evolve new defense mechanisms, Bassler said.

Such drugs might be valuable in a proactive strategy, said Neil Fishman, an infectious-disease specialist at the University of Pennsylvania School of Medicine.

That’s because some of these bacterial communicators are involved in the formation of biofilms, thin coatings that can stick to catheters and other hospital equipment.

These biofilms might someday be prevented by pre-treating catheters with quorum-sensing drugs, said Fishman, who was not involved in the new paper.

“I think there’s potential there,” he said.

Cholera works in an unusual way, said lead author Douglas A. Higgins, a graduate student in Bassler’s molecular biology lab. For most disease-causing bacteria, a high level of a chemical signal triggers a virulent response.

But with cholera, the bacteria are virulent to begin with, latching on to the intestinal wall and eventually forming biofilms. Once there are enough bacteria and their chemical message is strong enough, the bugs detach from the intestinal wall so they can leave the host and infect someone else.

While stopping some bacterial diseases will require scientists to inhibit a bug’s chemical message, the Princeton team realized that for cholera, they could simply administer the chemical message itself.

Its name is a mouthful: (S)-3-hydroxytridecan-4-one. Once Higgins isolated it, co-author Megan E. Pomianek figured out how to make it in the lab.

They successfully tried it on the cholera bacteria in a test tube, where it stopped the production of a toxin that allows the bug to attach to the intestines. The next step is to try it in mice with the disease.

An eventual therapy might involve a combination of the synthetic chemical message and a traditional antibiotic, the paper’s authors said.


Cholera is transmitted through unclean water and food, and can lead to severe diarrhea, nausea and dehydration. It can generally be treated with rehydration – drinking a mixture of water and electrolytes – and is rarely fatal in the United States.

But in developing countries, clean water for rehydration can be in short supply – the very reason cholera spreads there in the first place. Some recent epidemics have killed thousands. So a drug based on the new approach could be useful, Bassler said.

Other contributors to the paper included Princeton’s Martin F. Semmelhack and Christina Kraml, along with Ronald K. Taylor of Dartmouth Medical School.

While cholera is among the first big diseases to yield its language, Bassler’s lab and others are working to identify the chemical communicators for numerous pathogens.

“This paper specifically concerns cholera,” Higgins said. “But it provides proof in principle that we can do it with any bacteria.”

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AP-NY-11-15-07 1822EST