by Matthew Makowski
photo by Amanda Pitts

For the first time appearing in the U.S., a rare kind of E. coli infection that scientists are calling a “superbug” was found in May in a 49-year-old Pennsylvania woman. This “superbug” is resistant to many antibiotics, even Colistin, which doctors use as a last resort when other antibiotics aren’t effective.

Researchers said if the gene that made the E. coli drug-resistant, called mcr-1, passes to another superbug with other mutations, it could result in bacteria that resists all known antibiotics.

At Grand Valley, several chemistry professors, including Rachel Powers, Brad Wallar and David Leonard, and their teams of undergraduate students have spent the past 10 years researching solutions to antibiotic resistance in a different type of bacteria.

“The recent discovery of a superbug is a huge concern; these bacteria are now resistant to our last-line defense antibiotics,” said Powers. “In our lab, this has provided even more motivation to find novel ways that our research can contribute in the fight to overcome bacterial resistance.”

Analyzing antibiotics

While there are many different mechanisms of resistance, Powers’ team focuses on one specific type, beta-lactamase. Powers said these enzymes negate the healing powers of a genre of antibiotics known as beta-lactams.

“Most people are familiar with specific beta-lactam antibiotics, such as penicillin and amoxicillin. We’re looking at ways of taking the resistant bacteria that contain beta-lactamase enzymes out of commission by blocking the activity of the beta-lactamase,” Powers said. “Bacteria grow and multiply very quickly, and they’ve been around over the course of evolutionary time, so they have a lot of different resistance mechanisms.”

To block the activity of these enzymes, the researchers work to develop inhibitors that can be administered along with beta-lactam antibiotics. Powers said this specific research is challenging because there is no one-size-fits-all inhibitor due to the many different classes of beta-lactamase.

“There are big cavities and indentations in the 3D beta-lactamase models we use and we simply want to block up the cavities with inhibitors,” Powers said.

Crystallography at Argonne

To begin the inhibitor discovery and development process, Powers’ team first grows microscopic crystals in the chemistry labs at Grand Valley. These crystals are packed with the beta-lactamase enzymes.

The team takes the crystals to Argonne National Laboratory, a multidisciplinary science and engineering research facility near Lemont, Illinois. Specifically, this research is performed in collaboration with Argonne scientists at the Life Sciences Collaborative Access Team Beamline.

While it is not uncommon for academic researchers to reserve time at the lab, Powers said it is rare for faculty members to bring along undergraduate students to perform research at Argonne.

“Instead of shipping off our crystals to another lab, we were the ones actually collecting the data and learning from it.”
– Josephine Werner

Josephine Werner, a native of Sault Ste. Marie, graduated from Grand Valley in April with a bachelor’s degree in chemistry. She traveled to Argonne three times while working with Powers and said the experiences taught her how to conduct research safely and appropriately in a professional setting.

“Taking part in research that is done at a national lab is an experience that not many students from other universities can boast about,” Werner said. “I found a lot of value in these trips because instead of shipping off our crystals to another lab, we were the ones actually collecting the data and learning from it.”

At the facility, the team shoots high-energy X-ray beams through the crystals and measure diffraction data — a process called crystallography. This process allows researchers to study where inhibitors may be able to bind and prevent antibiotic resistance based on where the beams diffract off any given crystal.

This data is then used to create electron density maps showcasing the beta-lactamase enzymes within the crystals on an atomic level. The maps also show the locations where inhibitors could potentially bind to the enzymes.

Proper Rx

Werner said the team’s research is critically applicable to 21st century medicine, and she plans to continue exploring antibiotic resistance during graduate school.

“These bad enzymes work to destroy some of today’s most clinically relied-upon antibiotics,” Werner said. “Due to the use and misuse of antibiotics, many bacteria are resistant to them. Antibiotic-resistant strains are responsible for causing many deaths and inflicting high costs for health care facilities.”

Werner added that she plans to apply the knowledge she has gained through this research at Grand Valley to be a more effective physician.

“As a physician, I will be responsible for correctly prescribing antibiotics to my patients and having a background in chemistry and bacterial resistance to antibiotics will help me care for them,” Werner said. “My awareness of antibiotic resistance will help me make sure that I do not over-prescribe these medications or dosages.”