MILWAUKEE - When bacteria start talking, bad things happen.

Many bacteria release chemical signals in search of their "friends." When chemical levels remain low, the bacteria don't make much mischief. But when the bugs congregate, chemicals build up, which alerts the microbes that there are enough of them to kick off an infection.

These collective infections can be especially severe and hard to treat. But Helen Blackwell, a University of Wisconsin-Madison assistant professor of chemistry, thinks she's found a way to stop these bacterial social gatherings before they start.

By mimicking the chemicals that bacteria use to talk to each other, Blackwell is working to develop new drugs to trick the microbes.

And the approach has shown success.

Already, Blackwell's group has found many new compounds to block the chemical conversations behind two of the most common sources of hospital-acquired infections: methicillin-resistant Staphylococcus aureus, or MRSA; and Pseudomonas aeruginosa, an opportunistic invader of patients with compromised immune systems.

Drugs that target the microbes' social traits, rather than killing every individual, might offer another bonus in the fight against bacterial super-bugs: They should also slow the rate at which bacteria develop drug resistance compared with traditional drug approaches.

"You're not actually killing the bugs, so there's not the selective pressure in the same way," said Steve Diggle, a microbiologist at the University of Nottingham in England, who specializes in studying bacterial communication.

"You're targeting the group as a whole. You're tackling billions of individuals. So, it's a lot less likely that they'll evolve resistance."

RESPONSES TRIGGERED

The bacteria's communication system, known as "quorum sensing," triggers a wide range of responses, including virulence factor production, glowing bioluminescence and the formation of slimy bacterial mats called biofilms - the primary source of dental plaque and numerous chronic infections.

Importantly for Blackwell, a chemist trained in stitching together molecules, the bacterial chatter is spoken in the language of small molecules - a group of compounds that are smaller than proteins yet biologically active.

"Since the whole system is mediated by small molecules, it's like a sandbox for chemists to play in," said Blackwell, who was named one of Popular Science magazine's "Brilliant 10" last year.

To explain the game of synthesizing small molecules, Reto Frei, one of Blackwell's graduate students, grabbed a Sharpie pen and started scribbling on the glass front of the laboratory fume hood.

He sketched a thick, flat line showing the filter paper they use as base. The filter paper costs only pennies apiece, and it can be manipulated much more easily than traditional techniques dependent on resin-based substrates, Frei said.

Frei then drew in evenly spaced little spikes, or "mini skyscrapers" as he called them, in a spreadsheet-like grid on the paper. On top of the spikes, Blackwell's team mixes and matches chemicals to create vast arrays of different chemical combinations, he explained.

To make the chemicals react quickly, they pop the spotted paper into an industrial-grade microwave oven, which helps generate hundreds of molecules within a matter of minutes to hours.

"If you do traditional chemistry in solution, it would take a whole day to make one compound," said Thanit Praneenararat, another graduate student.

The dizzying array of new molecules alone is not the goal. "I'm most excited not about the novel compounds but about the novel activity," Blackwell said.

PROMISE SHOWN

Among all the new compounds Blackwell and her students have synthesized, a dozen or so are showing promising biological activity.

Some of these work well specifically against Pseudomonas aeruginosa and other related Gram-negative bacteria, the group that causes the majority of hospital infections.

Blackwell's approach starts with the microbe's own signaling molecule, which usually turns on biofilm formation at sufficient concentrations. But Blackwell makes slightly modified analogs to out-compete the natural molecule in binding to its receptor.

In this way, she found that by adding a large chemical ring "dumbbell" onto the molecule's tail, sprinkled with highly reactive halogen elements, she could significantly blunt the bug's signaling ability, both in a lab dish and inside other organisms.

For a study published online last month in the ISME Journal, Blackwell teamed up with Jo Handelsman, a University of Wisconsin-Madison professor of bacteriology and plant pathology, to show that her signaling inhibitors reduced Pseudomonas' infectivity of cabbage white butterfly larvae by more than 50 percent.

"This inhibitor is doing awfully well," Handelsman said. "It's pretty strong evidence that you can introduce a chemical inhibitor to block quorum sensing and pathogen induction."

Blackwell doesn't always want to turn the bacterial dialogue off, however.

For "good" bacteria, such as those that can slurp up pollution or manufacture biofuels, Blackwell and her research team are also looking for molecules that promote cell signaling.

As a glowing endorsement to this approach, Blackwell, with UW-Madison medical microbiology and immunology professor Edward Ruby, discovered a molecule that induces bacterial signaling in Vibrio fischeri, a luminescent bacterium that resides in the light organ of the Hawaiian bobtail squid.

In an as-yet unpublished study, Blackwell and Ruby added their molecule into the squid's sea water, and the organ lighted up like a neon sign. "We believe the compounds freely diffused up into the light organ of the animal, interacted with the bacteria," and made it glow, Blackwell said.

TAKING ON A KILLER

Blackwell is also turning toward preventing cell-cell communication in Staphylococcus aureus, the bacterium legendary for its highly resilient form, MRSA, which kills tens of thousands of people in hospitals every year.

Staphylococcus, however, is part of the so-called Gram-positive group of bacteria, a completely different class than Pseudomonas. As such, its cell signaling follows a different, more elaborate pathway than the simpler system of Gram-negative bacteria. "There are many more players involved," said Blackwell.

In June, Blackwell published a paper in the journal Organic Letters reporting synthesis of the first non-natural protein-like molecule that blocks part of the notorious super-bug's communication pathway.

"Helen (Blackwell) is an example of one of the very, very best chemists that works well with biologists," said Handelsman.

The goal in the long run, Blackwell said, is to develop her compounds into therapeutic agents.

Unfortunately, most large pharmaceutical companies are no longer involved in antibiotic research and development, because the drugs are not seen as profitable. Blackwell hopes academic-driven research can fill the gap.

This is especially urgent as current antibiotics are reaching the limits of their effectiveness with resistant bacterial strains continuing to spread around the world.

"It's reaching crisis proportion," Blackwell said. "This is going to become a real issue in the next decade."