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 that antibiotics target,
microbiologists had 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 pneumoniaea common
cause of deadly meningitis and other illnessesthat 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
cgmpllete resistance to antlbiotics, 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 Pep27, 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 [Pep27] 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
VnsR--autolysiin suicide pathway, possibly by increasing production of Pep27;
according to preliminary data from Tuamanen's lab. The investigators
demonstrated the potency of Pep27 by injecting it into the spinal cord of
rabbits with meningitis caused by S. pneumaniae. The peptide killed bacteria as
effectively as penicillin does, they found.
While natural peptides often make poor drugsmost are toxic or easily
degrade( by enzymes in the bodyinvestigator are learning how to construct
safe, stable peptides or small molecules that mimiic them. In theory, compounds
based on Pep27 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 Giilmore. J. Travis