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Taking aim at bacterial virulence factors

Antimicrobial drug resistance is pervasive throughout U.S. hospitals, due in large part to a drop in new antibiotics being approved. As a result, potentially deadly infections have evolved stronger resistance to existing antibiotics, especially in hospitals, according to the National Institutes of Health (NIH). Ninety thousand patients who develop an infection in the hospital die each year, as compared to 13,300 in 1992.

“The problem of antibiotic resistance is terrifying,” says Angela Brown, assistant professor of chemical and biomolecular engineering. “My goal is to find an alternative to existing antibiotics. Very few new molecules are employed in the fight against bad bacteria, and existing antibiotics are being prescribed more frequently, which leads to more drug resistance.”

Most pathogenic bacteria produce some type of virulence factor as they settle into their new home, such as a toxin that kills host cells, enzymes that convert host cell molecules into nutrients for the bacteria, or molecules that allow bacteria to bind to surfaces. Instead of looking for new compounds that kill bacteria directly, Brown wants to block this mechanism so the body’s immune system can knock bacteria out before they become a threat.

As a postdoc at the University of Pennsylvania, Brown and her colleagues investigated the toxin-producing properties of Aggregatibacter actinomycetemcomitans, which causes periodontitis.

In a 2012 article in the Journal of Biological Chemistry, Brown identified the mechanism that the bacterium employs to bind to cholesterol and kill white blood cells. Using surface plasmon resonance and differential scanning calorimetry, her team measured the leukotoxin’s interaction with cholesterol.

“Our goal is to see if we can prevent these toxins from killing the immune cells,” she says. “We hope to do this with other bacteria as well.”

With a grant from NIH, Brown and her students have created a peptide chain of 20 amino acids that binds to cellular cholesterol, blocking the identically shaped toxin chain from occupying the space.

Someday, Brown hopes, success in test tubes with individual cells will translate to a method of blocking virulence factors in all kinds of harmful bacteria, bypassing traditional antibiotic drugs altogether. It’s past time to find a new way to beat this invisible enemy, she says.

“Bacteria will always find a way to resist. If we don’t keep up with them, we could have a really big problem.”

Story by Manasee Wagh ’00
 

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Angela Brown, assistant professor of chemical and biomolecular engineering

As existing antibiotics are used more frequently to treat disease, says Brown, more bacteria are developing resistance to medications.