Who Will Stop The Mutant Microbes?

To scientists and doctors who thought they had annihilated such bacterial killers as tuberculosis and staph infections a decade ago with antibiotics, what's happening in hospitals today is more frightening than a late-night horror flick: The bugs are back. After 40 years of aggressively pushing antibiotics, doctors are now confronting bacteria that have mutated defenses against drugs. Of the 2 million patients who get infections in hospitals each year, up to 60% are struck by microbes that have become resistant to drugs.

The specter of patients dying from once treatable infections, plus a promise from the Food & Drug Administration to fast-track new antibiotics through the regulatory morass, has created a golden opportunity in the $20 billion worldwide antibiotics business. Such giants as Glaxo, Merck, Schering-Plough, and SmithKline Beecham are scrambling to bolster their antibiotics research and development, and they're searching the labs of small companies for prospects. In fact, large drugmakers are likely to come up with the first new drugs aimed at these "superbugs," created by adapting chemicals in their existing libraries to work against the resistant bugs--if only temporarily.

Yet in the long run, scientists are convinced that the best way to foil drug-resistant bugs is with medicines "that work through new mechanisms of action," says Keith A. Bostian, a former Merck & Co. R&D manager who is now chief operating officer of two-year-old drugmaker Microcide Pharmaceuticals Inc. The Mountain View (Calif.) company is one of a few working on gene-based schemes to outwit microbes. "Chemists have gone as far as they could incrementally refining these agents" and instead must mine biotechnology and genetics for new strategies, he says. Indeed, the future for antibiotics is "coming more and more from biology," says Steve M. Elliston, president of Micrologix Biotech Inc.

NEW ATTACKS. Some of the most intriguing of these approaches are coming from Micrologix, Agennix, Magainin, Xoma, and a handful of other small companies. They are combining high-tech medicine and a witches' brew of proteins from bees, sharks, cows, and even humans to create new weapons. These agents combat bacteria very differently from existing drugs--and that's what gives them so much promise.

Of the 30 new antibiotics the established drug industry claims it has on the runway today, most are variations on existing drugs, which work through several narrow mechanisms. But bacteria replicate at blinding speed--sometimes doubling in a few minutes. The process can produce genetic mutations that give bugs defenses against a given drug--making an enzyme that splits the penicillin molecule so it becomes harmless, for example. The bugs can then quickly pass on their genetic armor. Since most antibiotics are derived from cousins of bacteria, such as soil molds, it's probably easier for bacteria to develop a genetic defense.

Proteins, however, attack bugs in new ways. Many of them are cationic, or positively charged molecules, while most infectious bacteria are negatively charged. The electrical attraction pulls cationic proteins to the surface of bacterial cells where they force their way inside--in effect, busting the cells apart.

Michael Zasloff, founder of Magainin Pharmaceuticals Inc., observed in the late 1980s that frogs with open wounds could live in dirty water without developing infections. He called the proteins responsible "magainins," after the Hebrew word for shield, and later found similar chemicals in sharks. The company has since synthesized dozens of related compounds in the lab that show "as much activity against resistant strains as they do against susceptible strains," says CEO Jay Moorin. Magainin soon hopes to begin testing one of them on infected diabetic leg ulcers.

The reason mother's milk protects babies may make one of its proteins a good bacteria fighter. Houston-based Agennix is gene-splicing the milk protein lactoferrin, which suppresses harmful bacteria in babies' stomachs, and is searching for virulent bacteria against which it might be a good drug. Bacteria need iron to convert nutrients to energy, but this natural chemical appears to absorb excess iron, thus stifling bacterial growth. For bugs to mount a defense, notes Agennix CEO Roger D. Wyatt, they would need to create a new metabolism. That's "a lot more than a single-gene adaptation" and probably impossible, he adds. Similarly, Applied Microbiology Inc. has found that bacteriocins, derived from a milk protein, cause pores to form in a bacterium's cell membranes. The Brooklyn (N.Y.) company is working with Calgon Vestal Laboratories, a Merck subsidiary, to develop bacteriocins against impetigo and with Astra Merck to create a drug against the bacteria that cause peptic ulcers.

Still other proteins seem to turbo-charge the power of existing antibiotics. Micrologix, which uses cationic peptides created by fusing proteins from moths and honey-bee venom, and Xoma, working with a chemical called BPI, which is isolated from humans, have found that in lab tests their products amplify the effect of antibiotics on bacterial infections--for reasons scientists can't explain.

ONE-TWO PUNCH. Exploiting these natural molecules won't be easy. Typically, they are proteins, which can't be given orally because they are chewed up by enzymes in the gut. That could limit their use to topical creams, nasal sprays, or injectable forms. That's why drugmakers have concentrated on the more practical, so-called small molecules, or synthetic chemicals that can be given in pills.

Vaccines, however, may offer advantages over any drugs. By using the body's immune system to prevent disease, these remedies don't have resistance problems. To deliver a novel one-two punch to bacteria, UniVax Biologics Inc. in Rockville, Md., is testing a vaccine on people against some dangerous forms of staph that could help patients at risk develop antibodies and ward them off. Next year, it plans to start testing a therapeutic treatment developed by inoculating healthy volunteers with the same vaccine, then harvesting the antibodies they make. Those antibodies would then be used to treat patients suffering from the infections. OraVax, meanwhile, hopes to develop nose or ear drops or other topical remedies that protect like vaccines by stimulating immune cells on mucous tissues, such as nasal passages, which are common entry points for bacteria.

The ultimate defense against bacteria may well lie in the genes that transform them into killers. Microcide and Virus Research Institute in Cambridge, Mass., are on the cutting edge of the search for these "virulence" genes. Such genes turn on processes that are used only when bacteria invade and infect the body--when a bug attaches to the surface of the lining of the lung, say. VRI is first pinpointing these genes, then it will find chemicals that sabotage them. Disarming bacteria instead of killing them could avoid what now happens with antibiotics--a Darwinian survival of the fittest that results, in this case, in resistant bugs. The approach is so intriguing that several drugmakers, including Glaxo, are negotiating potential collaborations.

It's far too early to predict which of these new approaches will pan out. Magainin already suffered a stock-deflating setback this spring when one of its proteins failed to show much benefit against impetigo, although even competitors contend that magainins still have enormous potential. Nor is there any guarantee that the startups can raise the tens of millions of dollars they'll need to bring drugs to market. But as patients continue to die from infections that were once treatable, it's hard to imagine drugmakers backing off this quest until better bug killers are in hand.

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