Dr. Linda M. Stannard, Univ. of Cane Town/Photo Researchers
Madison, Wisconsin—Here in her lab on the University of Wisconsin campus, chemist Helen Blackwell and her colleagues are eavesdropping on the chatter among single-celled organisms. For a long time they just listened. Now they actively interrupt the rumble of bacterial communication for a variety of practical purposes—such as augmenting the good works of friendly bacteria and thwarting the designs of dangerous ones.
“These bacteria represent some of the simplest life-forms,” Black­well says, “and yet they are constantly signaling one another with chemicals, much the way animals and insects shoot out pheromones.” This signal communication, called quorum sensing, helps the bacteria determine when they exist in sufficient numbers to take action. For example, the common pathogen Pseudomonas aeruginosa,  a stalwart of the Blackwell lab and a frequent culprit in the most virulent hospital-acquired infections, must reach a certain population density inside its host before it mounts an attack.
The bacteria conduct an on-going census by repeatedly synthesizing and emitting a signal compound that sends the message “I’m here.” When enough of the organisms gather together in a confined space, the compound becomes so concentrated that it permeates back through the cell membranes to combine with receptors inside the bacteria. This event triggers cellular machinery to produce proteins that initiate the bacteria’s characteristic group behavior, and the hapless patient who contracted Pseudomonas suddenly becomes fatally ill. “If you infect immunocompromised mice with Pseudomonas,” Blackwell reports, “they are dead in about 48 hours.”Antibiotics may prolong life, but the drugs often fail to cure the infection because the bacteria quickly develop drug resistance. So Blackwell has focused on a different way to intervene: Isolate the signal compound, copy it synthetically in the lab, and then tamper with it to change its message. If the organisms were prevented from gauging their own numbers, Blackwell reasoned, they might back down.
“Pseudomonas have dozens of receptors, each with a different signal molecule,” she says, “and there is potential cross talk among them, so it’s a very complicated system.” Nevertheless, Blackwell’s group has managed to produce a “cocktail synthetic agent” that interferes with the complex quorum-sensing behavior. In early experiments, the synthetic compound slowed the rate of Pseudomonas infection in mice. A combination of the compound and an antibiotic produced “a synergistic effect,” she says, that worked better than either approach alone.
“When you knock out the quorum-sensing system, the organism doesn’t die. You’re not killing the bacteria, you’re just keeping them from behaving as a group,” Blackwell says. That is actually a good thing, she explains: “Since they don’t have to behave as a group to survive, you’re not going to see them develop resistance to the compound.”
On a yellow pad, Blackwell draws a portrait for me of a prototypical quorum-sensing signal molecule: a ring of carbon atoms attached to some hydrogen, nitrogen, and oxygen atoms, trailing off in a long tail composed of more carbon atoms. “We copy these in the lab,” she says. “Then we tinker with them, playing with the ring, putting in different sorts of constituents—different types of bonds, different types of tails—that nature can’t put in there.” Some of the 200 variants she has made have turned out to be duds, but others have coaxed strains of bacteria to behave in ways nature never intended, such as silencing themselves or becoming more acutely attuned to quorum-sensing signals.