The new antibiotics are synthetic forms of cephalosporin, a broad-spectrum antibiotic closely related to penicillin. They appear to kill bacteria by masquerading as components of the bacterial cell wall in order to deactivate an enzyme that functions as a key bacterial defense mechanism, the researchers say. In preliminary lab tests, the new antibiotics — the first to exhibit this mimicry mechanism — were effective against vancomycin-resistant MRSA, a rare but extremely deadly staph strain for which treatment options are extremely limited, they say.
"We are the first to demonstrate this unique strategy, which could provide a new line of defense against the growing problem of antibiotic resistance," says study leader Shahriar Mobashery, Ph.D., a chemist at the university. "As scientists, we’re trying to stay one step ahead of the bacteria. The more strategies there are to fight resistance, the better."
Besides fighting staph bacteria, the compounds have the potential to work against a wide range of other types of infectious bacterial strains that appear in health-care and community settings, he says. At least one of the cephalosporin compounds identified has entered Phase I clinical trials (human studies), but results are not yet available. More studies are needed before it can be marketed, Mobashery and his associates say.
MRSA (methicillin-resistant Staphylococcus aureus) was first identified in the early 1960s and has become a difficult superbug to tame. While searching for strategies to defeat it, Mobashery’s research group focused on an enzyme called penicillin-binding protein 2a (PBP 2a), which is unique to MRSA. Research by others showed that the enzyme, located on the bacterial cell membrane, acts as a key defense mechanism by helping the bug maintain a chemical barricade that is impervious to antibiotics.
Mobashery’s group recently discovered, in a study published in the Feb. 16 issue of the Journal of the American Chemical Society, that the enzyme interacts with certain components of the bacterial cell wall and that targeting these components might deactivate the enzyme, making the bacteria vulnerable to attack. Subsequently, the group identified a set of three novel cephalosporin antibiotics that appear to interact with the enzyme and also contain protein components that are similar to those of the bacterial cell wall.
The researchers then added the antibiotics to vancomycin-resistant MRSA and compared the results to those of another set of antibiotics belonging to a similar drug class (beta-lactams). The new antibiotics killed the bacteria, whereas the others did not, they say.
Based on lab studies, Mobashery believes that the novel antibiotics gained access to the enzyme’s active site by mimicking chemical components of the bacterial cell wall, which is largely composed of a polymer called peptidoglycan. Upon contact with the cell wall components, the antibiotics appear to trigger the enzyme to open. Once open, the antibiotics deactivate the enzyme, setting in motion a chain of events that eventually kills the bacteria, the researcher says.
More studies are needed to verify the details of this unique mechanism and to determine whether this mechanism is used by other antibiotics, he adds. So far, only three antibiotics — all of them cephalosporin derivatives — appear to function by this mimicry mechanism, says Mobashery, whose study was funded by the National Institutes of Health.
Antibiotic resistance is a persistent problem today, stemming largely from the overuse of antibiotics. Careful handwashing and other sanitation practices are considered a key to preventing the spread of MRSA and other hospital-based infections, according to the Centers for Disease Control and Prevention.
The American Chemical Society is a nonprofit organization, chartered by the U.S. Congress, with a multidisciplinary membership of more than 158,000 chemists and chemical engineers. It publishes numerous scientific journals and databases, convenes major research conferences and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio.
— Mark T. Sampson