Science & Technology: Pharmaceuticals
Fresh Strains of Unzappable Germs
But molecular clues could lead to more effective drugs
Ten years ago, Dr. Elaine Tuomanen began a molecular assault on one of the more mysterious secrets of bacteria. Her mission was to find out how some microbes escape the killer effects of antibiotics--and then to find a way to zap those tenacious bugs.
In the course of trying to answer these questions, Tuomanen found, alarmingly, that this ability to escape the effects of antibiotics has already appeared in certain strains of the bacterium Streptococcus pneumoniae, which is responsible for ear infections, pneumonia, meningitis, and other infections--and kills 40,000 Americans per year. The bacteria are "tolerant" of antibiotics, meaning they cannot grow in the presence of the drugs, but neither are they killed. Once treatment is stopped, they can sometimes flourish again. Tuomanen found that these strains have begun to spread among the general public. That could explain why some children who appear to be recovering from meningitis suffer relapses. "It is a very bad piece of news to have something circulating out in the community that's not treatable," says Tuomanen, who heads the department of infectious diseases at St. Jude Children's Research Hospital in Memphis.SIGNALING SYSTEM. Tuomanen also turned up encouraging news, however. "We have the beginnings of an answer" for a new way to tackle antibiotic-tolerant microbes, she says. In a recent report in Nature, she and her colleagues said they had uncovered an intriguing cellular mechanism that responds to antibiotics--a discovery that could lead to a new class of more effective drugs. "This is the first time this kind of signaling system has been found to play a role in a common organism's response to antibiotics," says Dr. Hugh Rosen, executive director of basic infectious disease research at Merck & Co., who was not involved in the research.
The findings raise new concerns about the spread of organisms that cannot be killed by existing antibiotics. Doctors and public health officials are already struggling with the emergence of strains of staph, Streptococcus, and other germs that shrug off attacking drugs as easily as umbrellas shed rain. In addition, researchers know that some bugs display tolerance, a lesser form of resistance. That is what Tuomanen is finding in the Streptococcus bacteria.
Until recently, however, bacteria resistant or tolerant to antibiotics have been a problem mainly in hospitals, explains microbiologist Michael S. Gilmore of the University of Oklahoma Health Sciences Center. In hospitals, doctors have a fighting chance of controlling the microbes' spread. But Tuomanen's discovery that the microbes are beginning to appear in the general public suggests that efforts to control the spread of resistant or tolerant bacteria could soon become more difficult.MYSTERY SWITCH. Tuomanen's discovery required years of painstaking work. Scientists had known since 1970 that penicillin and other antibiotics don't actually kill bacteria directly. Instead, the drugs somehow turn on a bacterial self-destruct program that causes the bugs to die. But what flips on the fateful switch? And why do some bacterial strains seem to lack the switch entirely? That is what enables them to tolerate antibiotics.
Tuomanen chose to work with Streptococcus bacteria. Five years ago, she began altering the germ's genes, hoping to develop a collection of strains in which each one of the bacterium's 2,000 genes was disabled. Within three years, she had a freezer full of some 10,000 such strains. Next came the time-consuming task of growing the altered strains in the lab and searching for those that could tolerate antibiotics. The idea was to determine which genes were part of the bacterial self-destruct mechanism.
The search bore fruit. Tuomanen and her co-workers first found that 25 mutant strains could survive when doused with antibiotics. Then they showed that one of those mutated genes was part of the elusive, long-sought self-destruct switch. It was the gene for a sensor molecule that perches on a microbe's outer membrane. When the sensor encounters evidence of an antibiotic, it starts a biochemical process that turns on the self-destruct switch--and the germ dies. But when that sensor is disabled, Tuomanen found, antibiotics do not trigger the signal that turns on the suicide switch. The biochemical process is what scientists call a "signal transduction pathway," one of many communication systems that perform vital tasks inside cells. Tuomanen's work "reminds us that the signal transduction pathway of bacteria is very important," says W. Gary Tarpley, vice-president for discovery research at Phamacia & Upjohn Inc.
Tuomanen then analyzed samples of Streptococcus microbes taken from sick people. She discovered that 2% of the bacteria harbored this sensor mutation. That meant they would not be destroyed by antibiotics--not even by the antibiotic vancomycin, which kills almost anything. "We were pretty shocked," Tuomanen says. Adds the University of Oklahoma's Gilmore: "What is really important is that she found that [the microbes] weren't just tolerant to penicillin, but to vancomycin as well."
Tuomanen already has preliminary evidence suggesting that kids who get meningitis from tolerant strains of Streptococcus tend to have more relapses. And she's now analyzing germs from sick kids to determine the extent of the problem.
Tuomanen has also stepped up the effort to reach her original goal: finding a new drug that can zap antibiotic-tolerant strains. It might be possible to find a drug that bypasses the mutated sensor and flips on the self-destruct mechanism directly. Or it might be better to jump-start the suicide genes at a later stage in the sequence of events leading to cell death, drug development experts say.
Either way, there's tantalizing hope that drugs using such approaches might make it tougher for mankind's microbial scourges to develop tolerance or resistance to drugs. As the struggle between man and microbe continues, Tuomanen's years of genetic sleuthing may eventually help tip the balance.By John Carey in Washington and Amy Barrett in PhiladelphiaReturn to top