Nicholas Johnson nearly died from what he thought was a shoulder sprain. Last year the 13-year-old from Stafford, Texas, made an awkward tackle in football practice and a few days later ended up in the emergency room with a fever of 104.6 degrees. Doctors, who had initially given him pain medication and a sling, now added antibiotics and a diagnosis of walking pneumonia. But Johnson only grew worse. When his parents rushed him back to the ER three days later, respiratory failure had set in and doctors put him on a ventilator. "Our pediatrician told us he might not survive," his mother, Janet, recalls.

Johnson did survive. But only after multiple surgeries, months of rehabilitation and permanent hearing loss in one ear. Doctors still don't know what touched off Johnson's illness--most likely, bacteria entered his bloodstream through a shoulder abrasion. But one thing is clear: what nearly killed the otherwise healthy teen was an increasingly common infection that standard antibiotics couldn't touch.

As recently as the 1980s, doctors thought they had bacteria licked. But the microbes have bounced back with a vengeance, developing resistance to the strongest of antibiotics. A study released over the summer reports that 70 percent of infections acquired in hospitals--the hot zone for disease transmission--can defy at least one drug. And the problem is seeping out into the community. Doctors report that people like Johnson are coming in off the street nearly every week. "We're having patients die as we watch them, because there's nothing to treat them with," says Dr. Joseph Dalovisio, head of infectious diseases at the Ochsner Clinic Foundation in New Orleans. Many of the big pharmaceutical companies have abandoned antibiotics research to focus on more profitable chronic conditions. But a small army of biotech companies is racing to fill the void, pursuing new treatments for everything from blood infections to tuberculosis. The question is whether they'll get there in time.

How did it come to this? The problem of drug resistance is as old as antibiotics themselves. Because bacteria, like humans, are diverse, drugs are rarely 100 percent effective against them. A compound that is 90 percent effective against a particular bacterium will control most infections. But as generations of bacteria are exposed to that drug, the resistant strains survive and multiply, making the treatment ever less effective. That's why penicillin, the world's first wonder drug, now cures only a small fraction of the ailments it was once prescribed for.

The easiest way to develop a new drug is to improve on an older one. Boston-based Paratek Pharmaceuticals is working on a new tetracycline, an antibiotic that is as safe as penicillin but capable of treating a wider variety of diseases. "Finding a new antibiotic is an area where small companies can really excel," says Dr. Stuart Levy, Paratek's cofounder. "We can focus all our efforts on it, and we don't have to go to our investors or stockholders and say, 'We have a billion-dollar drug.' We'll be happy with a few hundred million."

Tetracycline works by penetrating a microbe's cell wall, then latching onto and disabling its ribosome, a molecular structure required for reproduction. The new resistant microbes either have mutant ribosomes that prevent the drug from binding to them or a pump that expels the drug. But Levy and his team have developed more than 1,000 new molecules that aren't so easily foiled. If approved by 2008, as the company hopes, their first candidate will be used to treat a host of serious infections, including the increasingly common methicillin-resistant Staphylococcus aureus (MRSA), the disease that nearly killed Johnson.

Meanwhile, researchers are pursuing drugs that could keep some microbes from infecting people at all. Most bacterial cells contain a "master switch," a protein that commands other proteins to attach to human tissue and, in some cases, release toxins. Paratek has developed molecules that--in laboratory experiments--can bind to the master protein and disable it. Because the new compound doesn't have to kill the bacteria or keep them from reproducing, Levy believes it is less likely to breed resistance.

Other companies are turning away from chemical compounds altogether, hoping they can ramp up the body's own response to infection. At Georgia-based Inhibitex, for example, researchers are using human antibodies to battle the superbugs. Antibodies are "like scouts in an army," says CEO Bill Johnston. They identify an invader and signal the body's immune system to come in and destroy it. And unlike drug molecules, antibodies don't typically breed resistance. (That's why vaccines provide such long-lasting immunity.) Clinical studies suggest that Inhibitex's leading drug candidate, Veronate, can help protect premature babies from infections like MRSA in the neonatal ward.

Further down the line is the prospect of attacking bacteria with naturally occurring viruses known as phages. Phage therapy was practiced in the United States before antibiotics were developed 60 years ago, and it's still used in Poland and parts of the former Soviet Union. The viruses inject their DNA into bacterial cells, reproduce inside them, and then destroy the cells by exploding out of them. And unlike antibiotics, "phages evolve along with the bacteria," says Alexander Sulakvelidze, cofounder of Intralytix in Baltimore--possibly making resistance easier to overcome. Another advantage of phages is their specificity. Whereas traditional antibiotics destroy beneficial bacteria as well as harmful ones, phage-based treatments "will kill only the bad bugs," says Janakiraman Ramachandran, founder of GangaGen, which has offices in Palo Alto, Calif.; Ottawa, and Bangalore, India. The catch is that doctors might have to match every patient's infection with just the right phage. To address that problem, researchers are now trying to develop phages that will attack more than one type of bacteria.

While most for-profit companies target diseases of the industrialized world, philanthropic groups are tackling the much larger problems of the developing world. Armed with grants from the Bill and Melinda Gates Foundation and the Rockefeller Foundation, among others, the New York-based TB Alliance is developing one of the first new drugs against tuberculosis in more than 30 years. TB kills 2 million people annually and requires a six-month treatment regimen involving four different antibiotics. Patients often quit the regimen after two to three months, as they begin to feel better--speeding the emergence of drug-resistant strains. If successful, TB Alliance's new compound, PA-824, could cut treatment time by half. It's expected to enter clinical trials early next year.

Will these efforts be enough to stem the tide of antibiotic resistance? Some experts doubt it. "There is no shortage of good ideas," says Dr. Carl Nathan of New York's Weill Cornell Medical College. "But there's a shortage of opportunities to put them into practice." Many believe we need public measures to expand the market for antibiotics--tax incentives to spur research and development, extended patents for high-priority drugs, government purchases to protect manufacturers during periods of low demand. Congress will debate these and other proposals next year, as part of the so-called BioShield II initiative. Countless lives could hinge on the outcome.