Novel Structures May Provide Leads On Antibiotics For Treating Drug-Resistant Bacteria

BUFFALO, N.Y. -- Researchers in the Department of Chemistry at the University at Buffalo have, by rearranging the molecular structure of penicillin, recently synthesized several novel classes of penicillin-type chemical structures that may serve as fresh leads in the search for new antibiotics.

The new structures not only have the potential to serve as leads for drugs that could better fight drug-resistant bacteria, but may show scientists how to improve existing antibiotics.

"Despite the enormous successes that penicillin and related families of drugs have enjoyed over the last 50 years in waging their war on bacteria, there is now growing concern among the medical and scientific communities that these agents are rapidly losing their effectiveness," said Edward Turos, Ph.D., assistant professor of chemistry at UB and principal investigator on the project.

While penicillin still works well against certain types of infections, he pointed out that there is fear that many more strains of bacteria may eventually develop resistance even to penicillin.

"Penicillin kills bacteria by shutting down the enzymes they need to build their cell walls," he continued. "Without a strong cell wall, the bacterium literally explodes due to its internal pressure. However, these microorganisms have come up with some remarkable ways to protect themselves from the lethal effects of ß-lactam drugs such as penicillin."

According to Turos, the most common cause of penicillin-resistance is the production of ß-lactamases, defense enzymes that are manufactured in large quantities by drug-resistant bacteria.

"The ß-lactamases 'patrol' the bacterial cell in search of an invading drug molecule, which upon binding to a ß-lactamase, is rapidly neutralized before it can damage the cell wall," he explained.

In order for the drug to kill resistant strains of bacteria, it must evade the ß-lactamases. One approach is to administer penicillin with a powerful ß-lactamase inhibitor, which attempts to knock out the ß-lactamases, so that the drug can more effectively disable the enzymes involved in cell wall biosynthesis.

"The catch-22 is that while the ß-lactam ring endows penicillin with sufficient reactivity to kill the bacteria, it is also the Achilles heel that makes the drug susceptible to destruction by the ß-lactamases," said Turos. "We have noticed that all of the penicillin-type drugs studied to date have the reactive ß-lactam ring in the same location within the drug's 'molecular skeleton.' This makes it relatively easy for the bacteria to mass-produce ß-lactamases to quickly render the drug useless."

Traditionally, he explained, scientists have tried to improve the antibacterial properties of penicillin by synthesizing structural analogues, chemical compounds with similar overall structures, but which differ in the chemical groups around the four-membered ring.

Turos and his colleagues have taken a unique approach by altering the arrangement of atoms within the ß-lactam ring itself.

"By reconfiguring the ß-lactam ring, we have the opportunity to design large numbers of compounds that will perhaps be reactive enough to kill bacteria but resilient enough to withstand the destructive forces of the ß-lactamases," Turos explained.

He added that this research is likely to provide further insight into how to "chemically rejuvenate" existing ß-lactam drugs to help them keep their potency longer.

The UB scientists were recently awarded a research grant from the American Chemical Society to investigate these novel chemical structures.