Drugs order bacteria to commit suicide.

People have a misperception that bacteria are selfish, solitary creatures. In reality, they often live in large colonies and coordinate their activities. When conditions become overcrowded or food scarce, some bacteria may even make the ultimate sacrifice and kill themselves.

New research indicates that many, if not all, known antibiotics exploit this noble behavior. Elaine Tuomanen of St. Jude Children's Research Hospital in Memphis and her colleagues have identified a suicide program in one bacterium that penicillin and other antibiotics trigger. They've even discovered a small bacterial protein, or peptide, that they call a "death signal" because it commands the microbe to tear its cell wall apart.

These findings, say microbiologists, promise a rethinking of how antibiotics act and may lead to a new generation of drugs that more directly turn on bacterial-suicide programs.

"It's exciting," says Michael S. Gilmore of the University of Oklahoma Health Sciences Center in Oklahoma City. "We've bought into dogmatic views of how antibiotics work without really understanding the molecular principles behind them, which means we were searching for new antibiotics with blinders on."

By identifying the bacterial molecules antibiotics target, microbiologists developed an understanding of the immediate effects of most antibiotics. Some, such as penicillin and vancomycin, interfere with the construction of the bacterial cell wall, while many others inhibit protein synthesis within a microbe. Yet these actions only explain why antibiotic-treated bacteria stop growing, not why the drugs ultimately kill the germs, says Tuomanen.

For penicillin, biologists once thought that disrupting cell wall synthesis leads to a weakened wall that finally bursts. Over the past few decades, however, they've learned that penicillin-treated bacteria activate a class of their own enzymes, autolysins, to dissolve the cell wall. Indeed, almost all antibiotics indirectly trigger this autolysin response.

Treating bacteria with "penicillin is like handing them a gun. But if they don't pull the trigger, it's not going to work," says Tuomanen.

Last year, her group revealed crucial components of one bacterium's suicide program. The team worked with strains of Streptococcus pneumoniae--a common cause of deadly meningitis and other illnesses--that stop growing but don't die when treated with penicillin, vancomycin, and other antibiotics. This trait, called tolerance, receives little attention but is likely more widespread than complete resistance to antibiotics, says Tuomanen.

The investigators found that the tolerant bacteria had a mutation in the gene for a sensor protein called VncS. Together with a protein called VncR, VncS forms a suicide-signaling pathway in the bacterium. VncR normally holds autolysins in check. If something triggers VncS activity, however, the protein chemically modifies VncR such that it somehow releases the autolysins to chew up the bacterial cell wall.

In the January MOLECULAR CELL, Tuomanen's team identifies the signal that stimulates VncS. Called [Pep.sup.27], it's a peptide containing just 27 amino acids. Although S. pneumoniae constantly makes and secretes this peptide, the bacterial-suicide program normally stays off.

"We believe [[Pep.sup.27]] has to reach a certain critical concentration before the sensor sees it. That concentration is typical of when the bacteria are at high density," says Tuomanen.

Antibiotics such as penicillin and vancomycin somehow activate the VncS-VncR-autolysin suicide pathway, possibly by increasing production of [Pep.sup.27], according to preliminary data from Tuomanen's lab. The investigators demonstrated the potency of [Pep.sup.27] by injecting it into the spinal cord of rabbits with meningitis caused by S. pneumoniae. The peptide killed bacteria as effectively as penicillin does, they found.

While natural peptides often make poor drugs--most are toxic or easily degraded by enzymes in the body--investigators are learning how to construct safe, stable peptides or small molecules that mimic them. In theory, compounds based on [Pep.sup.27] or similar death signals in other bacteria would make effective antibiotics. "If we could pirate that death signal, we could trigger the [bacteria] to die," says Gilmore.