Last Updated

03 Jan 2003

Source: Wall Street Journal, April 11, 2002.

HEALTH

Toothless Germs Can't Bite: Scientists Research Antitoxins

By DAVID P. HAMILTON, Staff Reporter of THE WALL STREET JOURNAL

To stop an infection, most doctors automatically reach for an antibiotic, the most effective way known to kill off infectious germs.

But antibiotics are the nuclear weapons of medicine -- they often also wipe out helpful bacteria and foster the growth of drug-resistant germ strains. Some infections, such as anthrax , can also progress to the point that even eliminating bacteria with antibiotics won't save a patient's life.

That's why some scientists are increasingly interested in the study of bacterial toxins -- the tiny protein molecules produced by bacteria that cause most of the harm from infection. If researchers can find new and specifically targeted ways to neutralize those toxins, it might be possible to develop medicines that defuse infections without the unwanted consequences.

Last year's anthrax attacks are focusing new attention on toxin -- or rather antitoxin -- research, which is rooted in more than a century of study into what actually makes infectious organisms dangerous to humans. As a result, molecular biologists and chemists are expanding their efforts to identify and counteract a variety of "virulence factors" produced by bacteria in hopes of providing new weapons against many stubborn diseases.

"What this field is really bringing to light is a completely new concept in how to build antimicrobial therapies," says Jorge Galan, a microbiologist at Yale University.

Ultimately, Dr. Galan and other researchers hope to hold infections at bay by neutralizing virulence factors directly, thus reducing the need to kill large microbes indiscriminately with antibiotics. Hold down an infection this way long enough and the body's immune system will have the time it needs to eliminate the germs itself.

Among other advantages, drugs based on this approach could help prevent the spread of antibiotic resistance. Such resistance is a natural consequence of broad-spectrum antibiotics, which kill off harmful bacteria in droves but spare those with mutations that allow them to withstand the onslaught. Such mutant strains can proliferate and spread widely, making antibiotic treatment less effective.

New targeted drugs, however, might not even kill infectious bacteria directly, thereby easing the pressure that can lead to the emergence of resistance. Scientists such as Jeffrey Miller at the University of California in Los Angeles hope eventually to target the chemical signals that bacteria use to orchestrate their activity, raising the possibility that the right drug might jam those signals and thus block the process of infection.

That approach, while promising, is still a long way off. Not only are researchers still hard at work untangling a complex web of virulence-factor interactions, but any drugs that result are likely to be useful only against individual diseases, unlike antibiotics, which are effective against many classes of bacteria. To make effective use of such targeted drugs, doctors will also need ways to rapidly identify the microbes that cause a particular infection in order to prescribe the right drug.

Anthrax is a prime candidate for such work. Like most infectious agents, anthrax wreaks havoc by releasing toxic molecules that flow through the body, killing cells in vast numbers and eventually leading to hemorrhage and death. Antibiotics can easily kill the anthrax bacterium, but in advanced infections the toxins can linger -- one reason last fall's anthrax exposures led to several deaths in people who began antibiotic treatment too late.

To find other ways of preventing anthrax-related deaths, researchers have analyzed the structure of the anthrax toxin in great detail. It turns out that the toxin is assembled in the body from several separate proteins, all of which are harmless on their own. Once knitted together, however, the toxin punches holes in cells and kills them from the inside.

Late last year, a Harvard University team led by R. John Collier figured out a way to use a synthetic protein molecule that can "jam" the final assembly of the anthrax toxin, rendering it harmless in rats. At roughly the same time, James Young and a team at the University of Wisconsin also identified a "sticky" protein the anthrax toxin uses to penetrate cells. Drug companies can now screen for new drugs that would jam that protein as well, preventing the anthrax toxin from doing its damage, Dr. Young says.

A hunt for antitoxins is under way with other potential biowarfare agents, such as botulinim toxin and tularemia. The approach is also relevant to more common diseases such as cholera, diphtheria and pertussis, also known as whooping cough.

At the University of Texas, for instance, microbiologist Leon Eidels recently isolated a protein to which the diphtheria toxin latches as it kills cells, and is studying ways to use part of it as an antitoxin. Since diphtheria patients can still die after antibiotic treatment, Dr. Eidels hopes that injections of the toxin's receptor protein might bind up free-floating toxin molecules and prevent them from damaging cells.

Anthrax , of course, remains an extremely rare disease, and with luck other biowarfare agents will also remain uncommon. Antitoxins for diphtheria and pertussis, meanwhile, are needed only for patients who haven't already been vaccinated against the diseases. Most people in the U.S. have been vaccinated, with the exception of some immigrants. Largely for that reason, pharmaceutical companies haven't shown much interest in developing antitoxins until recently. Dr. Collier of Harvard, for instance, is still exploring ways to develop his experimental anthrax antitoxin as a treatment for humans, but months have passed without any progress.

Microbiologists such as Dr. Galan aren't discouraged, noting that bacterial toxins are only one type of virulence factor -- a much broader group of molecules that include such oddities as a set of proteins that form a kind of microscopic "syringe" that bacteria use to inject other proteins into a cell.

Since many bacterial virulence factors bear little resemblance to classic toxins that kill cells directly, Dr. Galan and other researchers figure that mapping out their interactions might make it possible to design narrowly targeted drugs that directly block the process by which germs cause disease.