A different approach to fighting antibiotic resistance

Assistant Professor of Chemistry Isabelle Taylor tackles antibiotic resistance with a dedicated group of students. Here she's pictured with Nicolas Zimmermann '27, one of the student co-authors on their recent Biochemistry publication. (Photo by Stephen Salpukas)

Every minute, nearly 500 antibiotic prescriptions are written in the U.S.

Many of these drugs succeed, but more are being outmaneuvered by resistant bacteria. This can lead to tragic results, like the death of one Nevada woman in 2017 after 26 treatments couldn't cure her infection.

As large pharmaceutical companies decrease investment in antimicrobial treatments, academics and entrepreneurs play an increasingly critical role in the fight against superbugs. This includes people like Isabelle Taylor, assistant professor of chemistry at William & Mary. She and her students are tackling the bacterium Pseudomonas aeruginosa, responsible for over half a million deaths globally each year. Their recent publication in Biochemistry advances an innovative approach to addressing antibiotic resistance.

Interrupting bacterial communications

Traditional antibiotics kill bacteria or target their growth and replication. While this strategy has worked well for decades, it can lead to resistance - when mutated bacteria survive and continue to replicate, unbothered by the treatment.

In recent years, scientists have begun investigating another idea: What if we don't kill the bacteria but instead interfere with their communications and prevent them from launching a coordinated attack on the host? This approach might make it harder for bacteria to develop resistance. It's the foundation of Taylor's approach, which targets quorum sensing (QS).

"Bacteria communicate with a chemical language, emitting molecules into their environment," said Taylor. "You can think of this like radio communications among soldiers on a covert mission. Once they realize enough of their comrades have landed, they can start to connect and behave as a unit. Bacteria do something very similar. Once a quorum has been reached, they begin to change their behavior, moving from acting as individuals to acting as a group. They form colonies and secrete toxins. It's this coordinated attack that ultimately makes us sick."

By understanding and interfering with how bacteria talk to each other, Taylor hopes to develop a treatment for P. aeruginosa, a particularly nasty bug.

Treatments for the most vulnerable

"P. aeruginosa is multidrug-resistant and a leading cause of hospital-acquired infections," said Taylor. "It thrives in all types of environments and often grows on catheters, stents or ventilators."

The pathogen is especially dangerous for the immunocompromised, cystic fibrosis patients and severe burn victims. And the World Health Organization includes carbapenem-resistant P. aeruginosa (carbapenems are a class of last-defense antibiotics) on their Bacterial Priority Pathogens List.

In their recent Biochemistry publication, Taylor, William & Mary Assistant Professor of Chemistry Katelynn Perrault Uptmor and several W&M student co-authors investigate new treatments for this bacterium by targeting QS.

"We're looking at two proteins that interact and play a critical role within the QS pathway. When they couple, these proteins help release a toxin, pyocyanin," said Taylor. "If we can disrupt their interaction, we hope to handicap the bacterium's ability to stage an infection."

Purchasing a set of 770 Food and Drug Administration-approved drugs, Taylor's team tested these small molecules against PqsE, one of the two aforementioned proteins. After performing several experiments, they identified three candidates for further development.

"These molecules all decreased the enzymatic activity of PqsE," said Taylor. "One in particular, Vorinostat, which is currently approved as a cancer therapy, even worked when incubated in bacterial cultures of P. aeruginosa," said Taylor.

This point is particularly important for future drug development. Gram-negative bacteria like P. aeruginosa have two cell walls, which act as a double layer of armor against drugs seeking to enter the cell.

Moving forward, the team will continue investigating these three molecules to understand how they bind structurally to PqsE. They will also begin to modify the structure of Vorinostat.

"We've shown that Vorinostat binds to the protein's active site - where it's performing reactions," said Taylor. "But we weren't able to disrupt PqsE's coupling with its QS partner, RhlR. By introducing small chemical adjustments to Vorinostat's structure, we are hopeful that we can disrupt its quorum-sensing activity and move closer to a new treatment."

Catherine Tyson, Communications Specialist

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