Developing new leads in the fight against antibiotic-resistant bacteria

A unique cell wall target yields promising results against Staphylococcus aureus

By Alexandria Daum

Project Investigators: Dr. Eric Brown, Dr. Natalie Strynadka and Dr. Gerard Wright

Dr. Eric Brown and his co-investigators have several promising leads in their novel approach to targeting methicillin-resistant Staphylococcus aureus (MRSA).

MRSA is a bacterial infection that is resistant to most antibiotic treatments, often occurring in healthcare settings such as hospitals or nursing homes, and also in the community. It is one of the leading causes of health-care associated infections worldwide.

The approach of Brown and his co-investigators is unique in that they are targeting a component of the cell wall that has not been targeted before called wall teichoic acid (WTA), a glycopolymer on the bacterial cell wall that is essential for the organism to survive and thrive. WTA plays a key role in resistance to antibiotics.

“We just think this pathway is ripe for more discovery,” explains Brown, a professor at McMaster University. “We can run chemical screens just looking for inhibition of growth of bacteria, but that doesn’t give us a lot of information. You want to put effort into something that is very selective.”

The synthesis of WTA consists of numerous steps – the idea is that by inhibiting one of these steps and disrupting the synthesis, the bacteria will become more sensitive to antibiotics.

This approach has already proved successful, as the team previously identified two drugs capable of reducing drug resistance in MRSA: clomiphene, a fertility drug; and ticlopidine, which can be used to prevent stroke. The next step will be optimizing these leads for potential clinical use.

“We think they’re not quite as potent as they need to be,” says Brown. “After all, these are cryptic activities. We think they’re great leads, though they might not be the end game, but they’re good starting points.”

Meanwhile, the team is doing more screening, both of synthetic and natural compounds, and Brown is hopeful that they will find more leads in this area.

“There’s already one known natural product that targets the first step in WTA synthesis but it’s not an ideal lead,” says Brown. “But it’s kind of proof-of-principle that natural products out there can halt WTA synthesis.”

The team is working on optimizing both clomiphene and ticlopidine in an effort to make the drugs more potent against MRSA. They are currently engaged in discussions with the U.S. National Institutes of Health on the potential of ticlopidine.

“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.”