New Antibiotics Put Bacteria in a Bind.

For decades, antibiotics have enjoyed "miracle drug" status, but because overuse and improper use are leading to increased bacterial resistance, many of these wonder drugs no longer work. However, recent studies at The Scripps Research Institute in La Jolla, California, may offer new hope for effective antibiotics.

Antibiotics work by destroying either the proteins that build a bacterium's cell wall or the protein-producing ribosomes. But resistant bacteria have altered their cell walls or ribosomes to withstand the drugs' action. So Chi-Huey Wong, a chemist at The Scripps Research Institute, decided to foil bacteria in a new way, by stepping in to the process earlier and preventing the creation of proteins in the first place.

In the 31 May 2000 issue of the Journal of the American Chemical Society, Wong and colleagues describe how they achieved this by targeting bacterial RNA, which builds proteins using information from the DNA. By binding aminoglycoside antibiotics to bacterial RNA, Wong is disrupting the synthesis of proteins at the point where resistance usually begins, and at the same time suppressing the creation of the bacterial enzymes that cause antibiotic resistance.

"We were interested in targeting the RNA, so we chose to study aminoglycosides since they are known to bind to RNA," says Wong. The aminoglycoside family, first discovered in the mid-1940s, includes streptomycin and neomycin. These antibiotics are usually injected or applied topically. The aminoglycosides are highly toxic, and particularly affect the ears and kidneys, although the damage they cause is usually minor and reversible.

Wong and colleagues chose to work with neamine, the simplest of the aminoglycoside antibiotics, structurally speaking. The group created several different dimers of neamine and tested them for their antibiotic activity and their ability to bind to RNA and disrupt protein synthesis. They identified several dimers of neamine that had high binding ability and were highly effective at killing bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus.

According to Wong, the new antibiotics inhibit the bacterial enzymes acetyltransferase and phosphotransferase, which modify the aminoglycoside antibiotics, allowing bacteria to withstand their threat. "When the antibiotic attaches to RNA in the ribosome, all enzymes and proteins in the bacteria can not be made properly, as the ribosome is the bacterial protein-making machinery," he says.

Wong also says that some of the new dimers are 1,000 times more effective than the original antibiotic. This means that not only will resistance development be suppressed, but also a much smaller dose of the drug will suffice for treating an infection.

Antibiotics have been the foundation for infectious disease therapy since the 1940s. In 1954, 2 million pounds of antibiotics were produced in the United States; today, more than 50 million pounds are produced. Two of the factors that contribute to antibiotic resistance are the overuse of these drugs in humans, animals, and agriculture, as well as failure to finish taking a prescribed course of antibiotics. Both long-term exposure to low doses and failure to finish a prescription encourage more resistant bacterial strains to flourish. Doctors prescribe more than 133 million courses of antibiotics each year to nonhospitalized patients.

The new dimers of neamine will soon be tested in humans. Wong says that the solution to antibiotic resistance will always be a temporary one, however, because it's just a matter of time before bacteria will evolve once again to survive. For now, though, Wong's research offers great promise in terms of providing a new direction for the development of novel antibiotics. What's more, says Wong, "There are more than a hundred antibiotics used to fight infections, and we might be able to exploit the same approach to develop any one of those to fight infections and even cancer cells."