Graduate student Emmy Nguyen works at a lab monitor in 蘑菇Av鈥檚 Bridges Lab. Drew Bridges watches in the background.

Researchers Identify New Target To Fight Antibiotic Resistance

By Caroline Sheedy Email Caroline Sheedy

Heidi Opdyke

Antibiotic resistance is a that makes common infections harder to treat and puts many medical procedures at risk. Now, 蘑菇Av researchers have uncovered a vulnerability in bacteria that could pave the way for an entirely new class of treatments.

The discovery, published today in , doesn鈥檛 kill the bacteria 鈥� a tactic that often leaves behind resistant survivors 鈥� but targets a key mechanism that controls bacterial behavior.

Drew Bridges, an assistant professor in 蘑菇Av鈥檚 Mellon College of Science, said the research could be an important tool in fighting a growing threat.

鈥淭raditional antibiotics work in a simple way 鈥� they kill bacteria,鈥� Bridges said. 鈥淚t's the same problem as with chemotherapy 鈥� the survivors cause problems. When you apply a bunch of antibiotics, a subpopulation of cells survives, they repopulate the population, and they're all resistant.鈥�

Bacteria are smarter than people think

Bacteria behavior is central to Bridges鈥� work. He said that people might think of bacteria as the simple organisms described in the pages of high school biology books. But bacteria are far more sophisticated 鈥� they take action, communicate and strategize for survival.

鈥淲e want to know if we can alter the actions that make bacteria infectious,鈥� Bridges said. 鈥淏acteria create biofilms that help them spread, stick to cells or swim into tissues. If we can shift those behaviors, maybe we can treat or prevent infections in a new way.鈥澨�

Bridges and graduate student Emmy Nguyen found a way to change behavior in Vibrio cholerae, the bacteria that causes cholera. They identified a pathway that regulates biofilm 鈥� sticky communities where bacteria can survive and thrive.

Drew Bridges and Emmy Nguyen stand in front of a lab bench and shelves, which are full of equipment and glass bottles. Bridges and Nguyen stand in lab coats with their arms crossed. They smile at the camera.
Drew Bridges and Emmy Nguyen

鈥淭hanks in part to biofilms, bacteria can grow in nearly every environment,鈥� Bridges said. 鈥淚f we can understand how that fundamental mechanism works, we could target that pathway to tip them into a weakened, less infectious state.鈥�

The study illuminated more about bacterial behavior, Nguyen added.

鈥淲hat makes this study so exciting is that this pathway doesn鈥檛 just control biofilms 鈥� it also regulates a wide range of bacterial responses, including metabolism, movement and stress defenses,鈥� Nguyen said. 鈥淲e think that when V. cholerae is in a hostile environment, activating this pathway helps it prioritize protection over proliferation.鈥�

Not just cholera

Cholera is a problem for many parts of the world without access to clean drinking water, and V. cholerae is an important model organism for studying infectious diseases. But Nguyen said it can be difficult to study infection because species differ so much from one another 鈥� the basic processes that drive the biofilm lifecycle may be different from those in other disease-causing microbes.

To determine if the pathway that controls the biofilm lifecycle in V. cholerae was found in other bacteria, Bridges and Nguyen turned to M. R. Pratyush, a graduate student working with Associate Professor of Biological Sciences N. Luisa Hiller. Pratyush completed a bioinformatic analysis and gave the team some good news 鈥� it is.

Two fluorescent green and yellow blobs against a dark blue and black background. The blobs are brighter and more yellow in the center and darker and greener at the edges.
A mutant strain of V. cholerae grows sprawling biofilms 鈥� dense bacterial communities that can make infections harder to treat.

鈥淭he protein that V. cholerae uses to control biofilm growth is also found in many other kinds of bacteria,鈥� he explained. 鈥淲hat鈥檚 interesting is that this biofilm protein belongs to a module composed of multiple proteins, and the whole module is found in many other bacteria. This means the way these proteins work together may be similar across many different species.鈥�

For Bridges and Nguyen, this information opened the door to explore how this shared mechanism might be used to control bacterial behaviors or lifestyle decisions.

From fundamental science to future solutions

The researchers teamed up with colleagues at the University of Pittsburgh to study how protein interaction within the pathway can influence bacterial lifestyle decisions. Then, working with scientists at Tufts University School of Medicine, they tested whether this pathway plays a role in infection.

At Tufts, the team compared normal bacteria (wild type) with versions that had the pathway activated (mutant). When they infected mice with these strains, they found that the mutant bacteria struggled to grow and colonize the host.

鈥淥ur goal is to activate this pathway and weaken the bacteria. To do that, we鈥檙e searching for small molecules that can turn the pathway on,鈥� Nguyen explained.

Looking ahead, the plans to build on these discoveries to design new types of treatments.

鈥淲e鈥檝e always been a basic science lab, focused on understanding how bacteria work,鈥� Bridges said. 鈥淏ut more and more, we鈥檙e thinking about how to translate that knowledge. Antibiotic resistance is a crisis, and developing new kinds of therapeutics that work differently is the direction we鈥檙e headed,鈥� he said.