Using antagonism to identify new ways of fighting superbugs

A unique approach to studying drug combinations has given GlycoNet researchers an exciting lead in the search for new drugs to treat Staphylococcus aureus.

Using an approach based on antagonism – studying drug combinations that work against each other – the researchers were able to identify that clomiphene, a popular fertility drug, inhibits the growth of S. aureus and improves the action of penicillin-like drugs against methicillin-resistant staphylococcus aureus (MRSA).

GlycoNet researchers Dr. Eric Brown (McMaster University) and Dr. Natalie Strynadka (University of British Columbia) were corresponding authors on a recent paper detailing the findings, published in the Proceedings of the National Academy of Sciences.

The researchers designed an innovative screen that sought compounds that suppressed the activity of targocil, an inhibitor targeting the pathways of cell wall biogenesis in S. aureus. Their approach not only allowed for the discovery of clomiphene, but also shed light on the biology involved in S. aureus cell wall synthesis.

“It’s a pretty unusual way to go about things,” says Brown. “The reason that we did it though is we could just look for things that kill bacteria. But the next big question is, how exactly is the compound leading to growth inhibition?”

S. aureus is one of the leading causes of healthcare-associated infections worldwide, with the rise of antibiotic resistant infections, such as MRSA, posing a significant threat. Brown says it is possible clomiphene could eventually be used clinically to treat MRSA, but what’s more exciting is the potential for new drugs.

“We just think this pathway is ripe for more discovery,” he says. “There’s a real crisis in terms of drug resistance that’s really changing modern medicine. There’s been no truly new drugs discovered for at least 30 years… If we take on truly new targets, we believe that will generate new chemical matter that will get around resistance mechanisms.”

Brown and Strynadka, along with Dr. Gerard Wright from McMaster University, have been funded for a GlycoNet project titled “Lead discovery targeting cell wall teichoic acid in Staphylococcus aureus.” This project will build on their recent discoveries to try and identify new targets.

“We’d like to do a larger-scale screen in order to develop this platform a little more thoroughly, generate multiple leads and then we can have our pick of what is the best target-lead combination,” Brown says. “We think our work’s not over.”