Counterattack: How Drugmakers Are Fighting Back

By LEON JAROFF

Doctors and the public were not alone in feeling cocky about infectious disease a decade ago. The drug companies did too. More than 100 antibiotics were on the market, and they had most bacterial diseases on the run, if not on the verge of eradication. So rosy was the outlook that U.S. government funding & for antibiotic research was declining, and many pharmaceutical firms were focusing on cancer and viral diseases, especially AIDS.

Observes George Miller, a microbiologist at the Schering-Plough Research Institute in Kenilworth, New Jersey: "What we in the pharmaceutical industry had been doing was to take existing classes of antibiotics and modify them to stay one step ahead of the bacteria." But that approach seems no longer able to stem the spread of drug-resistant bacteria.

Instead, researchers are employing several new strategies that they hope will put medicine ahead, at least temporarily, in the battle against the bugs. One approach is "rational" drug design, based on new understanding of how bacteria function at the molecular level. Using the techniques of biochemistry and crystallography, scientists are identifying bacterial genes and enzymes that confer drug resistance, and are creating antibiotics that will act specifically against a targeted microbe.

By discerning the molecular structure of an enzyme used by a drug-resistant bacterium to fight off that drug, for example, scientists can design a molecule that fits precisely into the active site of the enzyme. That neutralizes the enzyme, depriving the bacterium of a crucial element of its defense and making it susceptible once more to the original drug. "It's like sticking a wad of gum into a keyhole and binding it up," says Fred Cohen, professor of pharmacology at the University of California, San Francisco.

Scientists are pursuing a similar line of attack against viral diseases. In their AIDS research, for example, some are concentrating on a protein called CD-4, which resides on the surface of immune-system T cells where the AIDS virus attacks. Before the virus can enter T cells, it must join with a receptor site on the CD-4 protein. Here, too, a properly designed molecule might block that site and protect the T cell.

Some companies are delving into "combinatorial" chemistry, which involves making Lego-like blocks of chemicals that can be joined in hundreds of thousands of combinations, one or a few of which might create molecular havoc with a particular bacterium.

"Chemists have conceived of ways to build vast libraries of these wonderful combinations of building blocks, concepts that did not exist five or 10 years ago," says Barry Eisenstein, a vice president of the Eli Lilly research labs in Indianapolis, Indiana. Roboticized testing has helped make this approach practical by enabling researchers to screen hundreds of thousands of compounds in just a few months.

Prevention is even better than cure, and scientists are also experimenting with new vaccines that will ward off infections by alerting and arming the body's immune system against the invaders. One such vaccine is already on the market. It is designed to prevent the ills brought on by pneumococcus, which include sinusitis and ear infections as well as pneumonia.

Scientists are sanguine about regaining the upper hand against infectious disease but now realize that no strategy will work forever. As long as microbes have the ability to neutralize medicine's weapons, the drug companies will have to keep adding to the arsenal.

With reporting by Lawrence Mondi/New York