Fighting Superbugs: Scientists Target Bacterial Communication for New Treatments
Nearly 500 antibiotic prescriptions are filled every minute in the United States, a rate that underscores the escalating challenge of antibiotic resistance. The issue gained tragic clarity in 2017 when a Nevada woman died after failing to respond to 26 different antibiotic treatments, a case highlighting the growing ineffectiveness of these crucial medications.
As pharmaceutical companies scale back investment in developing latest antimicrobial treatments, researchers at academic institutions and entrepreneurial ventures are stepping up to address the crisis. Isabelle Taylor, an assistant professor of chemistry at William & Mary, is among those leading the charge. Her work focuses on Pseudomonas aeruginosa, a bacterium responsible for over half a million deaths worldwide annually.
Taylor’s recent publication in the journal Biochemistry details an innovative approach to combating antibiotic resistance: disrupting bacterial communication. Traditional antibiotics function by killing bacteria or inhibiting their growth. Though, this method often leads to the evolution of resistant strains, where mutated bacteria survive and proliferate despite treatment. Taylor’s research explores an alternative strategy – interfering with the signaling mechanisms that allow bacteria to coordinate attacks on the host.
“Bacteria communicate with a chemical language, emitting molecules into their environment,” Taylor explained. “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 exceptionally 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.”
Taylor’s team is specifically targeting quorum sensing (QS), the process by which bacteria assess their population density and coordinate behavior. P. Aeruginosa is particularly dangerous because it is multidrug-resistant and frequently causes hospital-acquired infections, thriving on medical devices like catheters and ventilators. The pathogen poses a significant threat to individuals with compromised immune systems, cystic fibrosis patients, and those suffering from severe burns. The World Health Organization lists carbapenem-resistant P. Aeruginosa – strains resistant to last-resort antibiotics – as a high-priority pathogen.
The research, conducted with William & Mary Assistant Professor of Chemistry Katelynn Perrault Uptmor and several student co-authors, focuses on two proteins crucial to the QS pathway. These proteins interact to release pyocyanin, a toxin. By disrupting this interaction, Taylor hopes to weaken the bacterium’s ability to cause infection. The team screened 770 FDA-approved drugs, testing their effects on PqsE, one of the two proteins involved. Three candidates emerged as promising leads, all demonstrating a reduction in PqsE’s enzymatic activity. Notably, Vorinostat, a cancer therapy already approved for use, showed effectiveness even when tested in cultures of P. Aeruginosa.
This finding is significant because Gram-negative bacteria, like P. Aeruginosa, possess two cell walls, providing a robust barrier against drug penetration. The team is now working to understand precisely how these molecules bind to PqsE and plans to modify the structure of Vorinostat to further enhance its ability to disrupt quorum sensing. “We’ve shown that Vorinostat binds to the protein’s active site—where it’s performing reactions,” Taylor said. “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.”