Dec. 22, 1999 Chemists at Wayne State University have designed two new drugs to fight the growing problem of antibiotic resistance: an antibiotic that "self-destructs" after exposure to light and another that "self-regenerates" after encountering resistant bacteria. Both represent novel approaches for keeping infectious bacteria at bay, the researchers say.
Reports on the research will appear in two separate peer-reviewed publications of the American Chemical Society, the world's largest scientific society. The report on the regenerating antibiotic is in the Dec. 22 print edition of the Journal of the American Chemical Society; the self-destructive antibiotic is scheduled for the Jan. 13 print issue of the Journal of Medicinal Chemistry. Both articles were published this month-Dec. 4 and 16, respectively-on the journals' web sites.
Antibiotics are among the most widely prescribed drugs worldwide. Commonly used to fight infections in both humans and animals, these drugs have had a major impact on public health. Paradoxically, their widespread use has fueled a growing health threat: antibiotic resistance.
"Once bacteria are exposed to a given antibiotic, they become resistant to its action in due time by changing their own genetic make-up to cope with the challenge," explains lead researcher Shahriar Mobashery, Ph.D., professor of chemistry at Wayne State University in Detroit. "The longer the bacteria are exposed to a given antibiotic, the higher the likelihood they will eventually evolve a resistance to that antibiotic," Dr. Mobashery said.
Antibiotic resistance means that drugs that used to work against infections will no longer work effectively, putting people and animals at risk. For years, scientists have been searching for ways to resolve this growing problem. Now, they may have found a duo of answers.
"A feature of antibiotics is that they are usually not metabolized in the body of the patient," explains Dr. Mobashery. "They are eliminated subsequently from the body and continue to select for resistant bacteria in the sewers and environment where they end up. The lingering presence of antibiotics has provided increased opportunities for bacteria to develop resistance to them in these environments."
Using a modified version of cephalosporin, which is structurally similar to penicillin and used to treat a wide range of diseases, Dr. Mobashery and his associates created a new type of antibiotic with built-in light sensitivity. The active portion of the drug was destroyed when exposed to light outside the body. In theory, this "self-destructive" mechanism limits the time that the antibiotic remains in the environment, reducing the forces that lead to development of resistance, the researchers say.
The researchers believe that antibiotics can be made self-destructive in other ways, such as making them sensitive to certain pH levels or other environmental conditions. The new approach has yet to be tested in humans or animals.
Dr. Mobashery and his associates also designed a new antibiotic based on a modified version of an aminoglycoside antibiotic, which is also commonly used to fight infection. Normally, resistance enzymes from disease-causing bacteria attack this antibiotic, rendering it inactive by adding an inhibitory group to its structure. The researchers' newly designed antibiotic receives the inhibitory group and releases it in a short time. Thus, the original active form of the antibiotic regenerates and remains effective at fighting bacteria.
The "self-regenerating" antibiotic fosters an environment in which the development of resistance enzymes in bacteria is no longer favored, thereby minimizing the threat, says Dr. Mobashery. "The common mechanism of resistance is not effective against this drug," he says.
Like the "self-destructive" antibiotic, the "self-regenerating" drug has yet to be tested in humans or animals. "Both these strategies represent proofs of concept, and many applications on these broad principles are possible in the future developments of anti-infective agents," Dr. Mobashery says.
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