Unusual Antibiotics Show Promise Against Deadly 'Superbugs'

The new antibiotics aresynthetic forms of cephalosporin, a broad-spectrum antibiotic closelyrelated to penicillin. They appear to kill bacteria by masquerading ascomponents of the bacterial cell wall in order to deactivate an enzymethat functions as a key bacterial defense mechanism, the researcherssay. In preliminary lab tests, the new antibiotics — the first toexhibit this mimicry mechanism — were effective againstvancomycin-resistant MRSA, a rare but extremely deadly staph strain forwhich treatment options are extremely limited, they say.

"We arethe first to demonstrate this unique strategy, which could provide anew line of defense against the growing problem of antibioticresistance," says study leader Shahriar Mobashery, Ph.D., a chemist atthe university. "As scientists, we’re trying to stay one step ahead ofthe bacteria. The more strategies there are to fight resistance, thebetter."

Besides fighting staph bacteria, the compounds have thepotential to work against a wide range of other types of infectiousbacterial strains that appear in health-care and community settings, hesays. At least one of the cephalosporin compounds identified hasentered Phase I clinical trials (human studies), but results are notyet available. More studies are needed before it can be marketed,Mobashery and his associates say.

MRSA (methicillin-resistantStaphylococcus aureus) was first identified in the early 1960s and hasbecome a difficult superbug to tame. While searching for strategies todefeat it, Mobashery’s research group focused on an enzyme calledpenicillin-binding protein 2a (PBP 2a), which is unique to MRSA.Research by others showed that the enzyme, located on the bacterialcell membrane, acts as a key defense mechanism by helping the bugmaintain a chemical barricade that is impervious to antibiotics.

Mobashery’sgroup recently discovered, in a study published in the Feb. 16 issue ofthe Journal of the American Chemical Society, that the enzyme interactswith certain components of the bacterial cell wall and that targetingthese components might deactivate the enzyme, making the bacteriavulnerable to attack. Subsequently, the group identified a set of threenovel cephalosporin antibiotics that appear to interact with the enzymeand also contain protein components that are similar to those of thebacterial cell wall.

The researchers then added the antibioticsto vancomycin-resistant MRSA and compared the results to those ofanother set of antibiotics belonging to a similar drug class(beta-lactams). The new antibiotics killed the bacteria, whereas theothers did not, they say.

Based on lab studies, Mobasherybelieves that the novel antibiotics gained access to the enzyme’sactive site by mimicking chemical components of the bacterial cellwall, which is largely composed of a polymer called peptidoglycan. Uponcontact with the cell wall components, the antibiotics appear totrigger the enzyme to open. Once open, the antibiotics deactivate theenzyme, setting in motion a chain of events that eventually kills thebacteria, the researcher says.

More studies are needed to verifythe details of this unique mechanism and to determine whether thismechanism is used by other antibiotics, he adds. So far, only threeantibiotics — all of them cephalosporin derivatives — appear tofunction by this mimicry mechanism, says Mobashery, whose study wasfunded by the National Institutes of Health.

Antibioticresistance is a persistent problem today, stemming largely from theoveruse of antibiotics. Careful handwashing and other sanitationpractices are considered a key to preventing the spread of MRSA andother hospital-based infections, according to the Centers for DiseaseControl and Prevention.

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