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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.