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Resisting Resistance

Another new way to attack antimicrobial resistance is to design drugs that disable the antibiotic-resistance mechanisms in bacteria. Patients would take these drugs along with antibiotics already on the market, making them effective again. For instance, Microcide Pharmaceuticals, the antibacterial company begun in 1992, is focusing on this approach against four organisms-staphylococci, enterococci, pseudomonas, and streptococci-which together account for 44 percent of the 2 million infections that occur each year in U.S. hospitals.

One resistance mechanism Microcide is concerned with is the elaborate method Pseudomonas aeruginosa has developed to resist many antibiotics. This bacterium causes a variety of diseases, including pneumonia and infections of the skin, urinary tract, and bloodstream. The resistant microbe has evolved in such a way that it has hundreds of pumps that bind to antibiotics as they enter the bacterial cell. The pumps literally eject the medicine from the cell. Each bacterium can have as many as four variations of the basic pump.

To target and disable the pumps, the researchers first had to thoroughly understand the pumps’ molecular biology. The investigators learned that often the pumps “recognize more than one type of antibiotic,” says Keith Bostian, Microcide’s founding scientist. “Some pumps recognize all the antibiotics.” A crucial factor therefore became making sure that the inhibitor Microcide was developing would inactivate all four pumps.
This past fall Microcide screened and tested a variety of chemicals that inactivate the pumps. Bostian says the company is close to picking its best candidate for drug development and that clinical trials might occur next year, with the product possibly on the market three to four years later.

These are just a few examples of the potential new drugs many pharmaceutical companies are hoping will get to market and prove successful in holding the line against antibiotic-resistant bacteria. But just how much help the public can expect and how soon is hard to predict. “I couldn’t honestly say whether I’m optimistic or not that they are going to fill the gap in time,” says Joshua Lederberg, who chairs the Institute of Medicine’s Forum on Emerging Infections and is a Nobel laureate. Because details of companies’ work are private, he says “there is no way to gauge how far along they are.”

Meanwhile, one approach to controlling infectious diseases that has been underutilized, Lederberg says, is preventive vaccines. He points to the success of the vaccine against Haemophilus influenzae type b (Hib). While the microbe sounds as if it causes the flu, it actually was the leading cause of meningitis, a potentially deadly disease, in U.S. infants during the 1980s. It also causes blood poisoning and pneumonia. Claire Broome, deputy director of the CDC, notes that the number of U.S. Hib cases in the ’80s was on the same order of magnitude as polio cases before the polio vaccine. Now, she says, “The [Hib] vaccine has almost entirely wiped out Hib meningitis.”

At least two drug companies are developing another bacterial vaccine, this one against pneumococcus, the leading cause of pneumonia and meningitis for all age groups in the United States and the most common bacterial cause of otitis media, middle-ear infections in children. Ear infections are a major reason for office visits to pediatricians, the prime cause of emergency-room visits for kids, and a common reason doctors pass out antibiotics. “If this vaccine is successful in preventing otitis media, that would be a tremendous step forward,” says Broome.

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Tagged: Biomedicine

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