Bringing Back The Glory Days For Antibiotics

That's what University of Guelph Microbiology Prof. and Department Chair Anthony Clarke, along with Profs. Gary Dmitrienko and Thammaiah Viswanatha of University of Waterloo's Chemistry Department, have set out to discover. Their research focuses on defeating the mechanisms that disease-causing bacteria have evolved to evade beta-lactam antibiotics. Beta-lactam antibiotics include drugs such as penicillin and cephalosporins.

"Bacterial resistance to antibiotics is a major problem today in the clinical therapy of infectious diseases," says Clarke, a member of the Canadian Bacterial Diseases Network. "There could soon be no effective antibiotics available to treat some major pathogens."

The culprits are beta-lactamases -- enzymes produced by the bacteria which render these antibiotics ineffective. Beta-lactamases can be easily transferred between bacterial species, a fact which worries Clarke.

Hailed as the new "wonder drugs," antibiotics were first used on a mass scale after World War II to treat maladies ranging from the common cold to serious burns. In some cases, such as for the common cold, the prescription was inappropriate, while in others patients would often not finish their prescribed round of antibiotics. Therefore, bacteria which were not resistant to antibiotics would be killed off, while the resistant bacteria would survive to pass their genes onto the next generation. Humans only began to realize how serious this problem was in the 1970s. But by then, resistant bacteria were already evolving at breakneck speed.

There are four classes of beta-lactamases: A, B, C, and D. Many researchers have already developed successful inhibitors for the A, C, and D beta-lactamases. However, the class B beta-lactamases have not yet been conquered, due to their unique "metallo" structure which contains zinc at the active site. These B beta-lactamases will be the major focus of Clarke, Dmitrienko, and Viswanatha's research -- among the first research of its kind.

Their strategy is to design target enzyme-activated inhibitors similar in structure to penicillin and the cephalosporins. Beta-lactamases will bind to and cut these inhibitors in the same fashion as for the antibiotics. The cleaved inhibitors will then rearrange to produce an activated compound which will attack the beta-lactamase enzyme and destroy it. The researchers believe this will allow co-administered, intact antibiotics to reach and wipe out the invading bacteria. Dmitrienko has already designed several promising compounds, but the researchers are hoping to develop even more potent substances.

"The re-emergence of old pathogens threatens the quality of life in our society," says Clarke. "Last year multiple-drug resistant tuberculosis became a problem in New York City. Recently, there was an outbreak of vancomycin-resistant Enterococcus at Scarborough General Hospital -- just when we thought it was under control. For these reasons we need to continue to develop both new antibiotics and effective methods for preventing antibiotic resistance."

This research is sponsored by the Strategic Grants program of the Natural Sciences and Engineering Research Council (NSERC).