Mycobacterium tuberculosis. Plasmodium falciparum. Staphylococcus aureus. Streptococcus pneumoniae. Enterococcus faecium. Neisseria gonorrhoeae. The list of microbial scourges that have developed immunity to one or more of the drugs used to treat them is growing ever longer, and in a number of cases physicians are running out of options. In U.S. hospitals, more than 20% of all enterococcus infections, which include infections of the gastrointestinal tract, heart valve and blood, are now resistant to vancomycin, for many years the antibiotic of last resort. Even more worrisome, insensitivity to vancomycin-which nurses and physicians in intensive-care units refer to as the big gun-is showing up in the dangerous family of staphylococcus bacteria.

That's the bad news. The good news is that help appears to be on the way, and with a little luck it might just arrive in time. For after years of paying scant attention to infectious diseases, pharmaceutical companies have begun to comb through the vast chemical libraries assembled over the past decade in search of new antimicrobial agents. The effort is starting to pay off. Since September 1999, the U.S. Food and Drug Administration has approved two new antibiotics that target both the enterococci and staphylococci. One-linezolid-seems particularly promising; it represents the first new class of antibiotics to come on the market in 35 years.

Many more such breakthroughs are needed, however, especially for diseases, such as tuberculosis and malaria, that are raging out of control in much of the world. It is sobering to note that more than 400 million people fall ill with malaria each year; of these, up to 3 million die, most of them children. With resistance to once effective antimalarials like chloroquine now widespread in Asia, Africa and South America, the prognosis could not seem more grim. "We're in a desperate situation," says Robert G. Ridley of the Swiss-based Medicines for Malaria Venture.

What makes the situation so desperate, experts agree, is that new and more effective drugs are not, in themselves, enough. As Richard Colonno, vice president of drug discovery for infectious disease at Bristol-Myers Squibb, sees it, what new drugs do is reset a pathogen's biological clock. They buy time, but eventually resistance to these compounds will also arise.

Why? In a word, evolution.

Modern medicine has engaged disease-causing microbes in an escalating arms race, so that as soon as drug developers launch a new weapon-an antibiotic, for example-their microbial foes respond by shoring up their own defenses. Sometimes bacteria and parasites undergo random mutations that spontaneously confer resistance. More frequently, they acquire survival-enhancing characteristics in the process of exchanging dna with other microbes that have already developed resistance.

Bacteria and parasites do not do this on purpose, of course, but the effect is much the same. In 1944, for example, penicillin appeared to be a magic bullet against staphylococcal infections. The problem was, it failed to kill every single bug, and those that survived the onslaught slowly began to multiply. The result: by the 1950s most staph infections had become highly resistant to penicillin. The same fate met penicillin's successors, erythromycin and methicillin; now it appears to be vancomycin's turn.

For this reason, it is not enough to come up with new drugs; it is also imperative for us to try our utmost to extend their useful lifetime. This means we must stop misusing them. Consider the case of penicillin. For decades, it has been prescribed by many physicians for every sniffle and sneeze, even when the source of the problem was a virus. Antibiotics have been recklessly prescribed for ear and even sinus infections, many of which, as Mayo Clinic researchers recently noted, are not due to bacteria at all but to the immune system's response to fungal infections (see box).

To make matters worse, antimicrobials have been introduced into hand creams, household cleansers, livestock feed. Not long ago, the fda's Center for Veterinary Medicine announced plans to withdraw approval of the use of fluoroquinolones in poultry feed. Of particular concern was campylobacter, a common cause of diarrheal disease. And the Minnesota department of public health made headlines when it surveyed poultry on sale in the state's supermarkets and found 70% of the samples were contaminated by campylobacter, 20% of which were fluoroquinolone resistant.

Overuse is just part of the problem, however. The evolution of resistance really goes into fast-forward when patients with serious diseases like malaria and TB do not follow doctor's orders, often because they are poor and cannot afford a full course of medication. Instead, they take just enough medication to alleviate their symptoms but not enough to rid their system of the original infection. This has the effect of eliminating the drug-sensitive microbes from the lineup and encouraging the drug-resistant ones to grow.

The current attack against resistant strains is multipronged. Some microbiologists are trying to re-engineer the older generation of miracle drugs to get around the mechanisms of resistance. Tetracycline, which kills bacteria by disabling a cellular structure known as the ribosome, is the target of one such effort. Bacteria become resistant to tetracycline, observes Tufts University microbiologist Dr. Stuart Levy, by deploying one protein that serves to shield the ribosome and another that acts as a molecular pump, forcibly ejecting the antibiotic from the cell. Those insights have spawned a line of tetracycline analogs, against which neither the shield nor the pump is effective. Boston-based Paratek, the company Levy helped found, is working with GlaxoSmithKline to develop these analogs into drugs.

Other companies are starting to look for fresh new antimicrobial agents. Cubist, in Cambridge, Mass., has an injectable form of one such agent-daptomycin-in late-stage clinical trials. Like tetracycline, it was derived from filamentous bacteria that dwell in both soil and water. But daptomycin does not work as tetracycline does by inhibiting cellular metabolism. Rather, it disrupts the conformation of the bacterium's cell membrane, more like penicillin. The way daptomycin does this appears to be unique; in other words, the resistance that disease-causing bacteria have developed to penicillin should not readily transfer to daptomycin.

Nature is not the only lode that drug developers are mining. Linezolid, the novel antibiotic just approved by the fda, is totally synthetic, and that is a great advantage, believes Pharmacia Corp.'s Dr. Gary Tarpley, who led the team effort that produced the drug. "Because this compound has never been seen by bacteria," he says, "it is extremely unlikely that there is any pre-existing resistance out there." Like tetracycline, linezolid blocks protein synthesis, but it does so much earlier in the cellular cycle. No other antibiotic operates in this fashion, yet another reason to expect resistance to develop more slowly.

Both daptomycin and linezolid (branded under the trade names Cidecin and Zyvox) are aimed at drug-resistant enterococci and staphylococci, which have ballooned into a huge problem for nursing homes and hospitals. But while that is the most attractive commercial market, a number of American pharmaceutical companies are also participating in private-public partnerships aimed at resolving the global health crisis created by drug-resistant malaria and TB. At present, neither disease is a tremendous problem in the U.S. or Western Europe, but that happy situation may not last forever, especially where TB is concerned. In 1992, at the height of a mini-epidemic in New York City, 3,800 new cases of TB erupted; hardest hit were aids sufferers and the homeless, as well as prison and hospital populations, a third of whom showed drug resistance.

Until recently, the outlook for patients with drug-resistant TB could not have been gloomier. The last major anti-TB drug, rifampin, was approved more than a quarter-century ago. In the interim, the TB bacillus has managed to develop resistance to the cocktail of drugs physicians have long used to treat it, including that old standby streptomycin. New drugs, with different mechanisms of action, would be a great help, particularly if they shortened the present six months' time required for treatment. The linezolid family, for example, appears to hold some promise, as does a compound the Seattle-based PathoGenesis Corp. is investigating.

The process of discovering antimicrobials should speed up, thanks to the rapid sequencing of the genomes of disease-causing organisms. Among the latest conquests are the bacteria responsible for causing syphilis and leprosy. The genome of the parasite that causes malaria is also beginning to yield its secrets, including the exact genetic mutations that confer chloroquine resistance. Scientists are beginning to exploit what they know about the parasite's life cycle after it invades the red blood cells of the human body. Daniel Goldberg, a malaria researcher at the Howard Hughes Medical Institute in Chevy Chase, Md., is trying to figure out how to block the parasite's digestion of hemoglobin and thereby cause it to starve.