By David N. Leff

If Streptococcus pneumoniae were a person instead of a pathogen, this pneumococcal bacterium might well be indicted for genocide.

It kills over a million people a year worldwide, mostly the very young and very old. That microbial atrocity statistic includes 44,000 victims in the U.S. The majority of them are children under two years of age - too young to benefit by the anti-pneumococcal vaccine available to their elders.

"Strep pneumoniae," observed microbiologist Michael Gilmore, "is ordinarily resident in many of us, without causing disease. It's usually inhaled, and resides in the nasal mucosa. That pneumococcus causes a lot of diseases related to inhalation, such as pneumonia, obviously. But it also is a leading cause of meningitis, an infection of the cerebrospinal fluid [CSF] and the brain."

Gilmore, an endowed professor of microbiology, immunology and ophthalmology at the University of Oklahoma Health Sciences Center, in Oklahoma City, is first author of a "News & Views" editorial in the current issue of Nature, dated June 10 and titled: "Antibody resistance: A vancomycin surprise." It comments on a research paper in the same issue, bearing the title, "Emergence of vancomycin tolerance in Streptococcus pneumoniae." The article's senior author is infectious diseases specialist Elaine Tuomanen, at St. Jude Children's Research Hospital, in Memphis.

"One of the things that this paper really sheds a little bit of light on," Gilmore told BioWorld Today, "is that we've not really understood precisely how cell-wall-active antibiotics work. We know for instance that penicillin and related antibiotics bind a protein on the surface of the bacterium's cell, and the job of that protein is to knit the cell wall together. When you inhibit that ability to knit the cell wall as the cell is growing, that, in and of itself, isn't enough to actually kill a pathogenic organism. What happens, this research shows, is apparently that blocking the ability of the bacterium to sense that inhibition - if it can't tell if that knitting together is blocked - then the bacterium doesn't commit suicide. Rather, it now becomes tolerant to the antibiotic."

Streptococci, Gilmore explained, "have a capsule, a heavy slime coating, that's a polysaccharide in nature. That layer is thought to be the primary virulence factor of pneumococci. The way it works is it prevents the phagocytic immune cells that gobble up bacteria and other things from being able to ingest it. The phagocyte tries to take a bite out of the bacterium, which escapes because its attacker can't get a good grip on that slime.

"The existing pneumococcal vaccine is targeted to that slime coating," Gilmore said. "The pneumococcus, once it establishes and builds its slime coating so it can't be removed very easily, starts producing some toxins. These begin to destroy tissue. This causes inflammation, which leads to more tissue destruction. The antibiotic's goal is to kill the bacteria, or prevent it from producing more toxins.

"What the paper says is this," the Oklahoma scientist continued. "With many antibiotics that are lethal for bacteria, the bacteria aren't killed directly by the antibiotic, but are tricked into committing suicide. What the St. Jude researchers did was blind the bacteria to the ability to detect the presence of these antibiotics. And when they did this, the bacteria didn't commit suicide. Instead, they became tolerant to the antibiotic.

"Probably the most important thing that we're beginning to realize," Gilmore said, "is that bacteria are really sentient organisms. They can sense their environment and respond. They sense it, by using a series of ports that allow them to sample the environment. It turns out that pneumococcus has seven or eight of these sensory protein windows. What the co-authors did was, they knocked those ports out, one at a time. And they found that when they knocked one in particular out - a bacterial mutant gene called vncS - the bacteria became tolerant to all of these antibiotics, in particular to vancomycin."

Unlike antibiotic resistance, the paper stated, "Antibiotic tolerance, the ability of bacteria to survive but not grow in the presence of antibiotics, is a precursor phenotype to resistance." And, once the drug is withdrawn, the bacterium resumes its growth and virulence.

The co-authors noted that pneumococcal meningitis is 30 percent fatal, and must be treated with bactericidal antibiotics, notably vancomycin. They inoculated rabbits intrathecally (into the spinal fluid), with either a vancomycin-sensitive strain of the bacteria, a tolerant strain or an equal mixture of both. Twenty-four hours later, untreated animals had acute meningitis.

When then given three intravenous injections of the antibiotic six hours apart, it killed the sensitive strain. However, "Twelve hours after the last vancomycin injection, the number of tolerant bacteria increased [by two logs per milliliter], indicating that therapy had failed."

Confronting the dire outlook that vancomycin may soon be painted into the same corner with its now resistance-bedeviled predecessor antibiotics against pneumococci, researchers are girding their academic and pharmaceutical loins to devise countermeasures on two fronts.

Humans Fight Back At Sentient Microbes

"Currently," Gilmore said, "a variety of efforts are under way to improve the vaccine. Right now, it's made up of the bacterial capsule carbohydrate. Unfortunately, our immune system prefers protein targets, so people are trying to link the carbohydrate to a variety of carrier proteins that'll cause a better immune response. And new classes of antibiotics are currently being tried. One that targets a new step in protein synthesis is called Linezolid. It's being tested right now by Pharmacia & Upjohn, of Kalamazoo, Mich., in an ongoing Phase II clinical trial, particularly for gram-positive organisms related to antibiotic-resistant pneumococcus."

Gilmore's own lab is working on the enterococcci. "There's very little research going on in enterococcal resistance," he pointed out. "And that's a particular problem."

He is organizing the first international American Society of Microbiology conference on enterococci. It will be held in Banff, Canada from February 27 to March 2, 2000.

"The meeting's agenda will cover three things," Gilmore said. "Pathogenesis, the ability of the organism to cause disease; biology, its mechanics, and antibiotic resistance; how it gets around treatment.

"There are strains of enterococcus that are now completely untreatable. In these kinds of infections, we are back to the pre-antibiotic era. We can't beat back these bacteria. So, it's very important that we put a lot of energy into the development of new antibiotics and new approaches to therapy."