PUBLISHED RESEARCH: George Mason researchers advance search for new antibiotics to combat drug-resistant superbugs
As antimicrobial resistance continues to threaten modern medicine, researchers at George Mason University’s College of Science are helping develop a new generation of antibiotic candidates aimed at some of the world's most dangerous bacterial pathogens.
A new study published in ACS Infectious Diseases and featured on the journal's July cover investigates potential treatments for infections caused by Acinetobacter baumannii and Klebsiella pneumoniae—two drug-resistant bacteria that frequently cause serious hospital-acquired infections and are increasingly resistant to existing antibiotics.
The study, a collaboration among George Mason University, the Walter Reed Army Institute of Research, and George Washington University, focuses on the bacterial MEP pathway, which is absent in humans, making it an especially promising target for new antibiotics. The George Mason team included Robin Couch, associate professor of chemistry and biochemistry; PhD graduate students Misgina Girma, Allyson Dailey, Haley Ball and Archi Sehgal; and undergraduate student Mosufa Zainab.
"What excites me most is that the MEP pathway gives us an opportunity to pursue an antibiotic strategy that is fundamentally different from those used by many existing drugs,” said Couch. “At a time when resistance is steadily eroding the effectiveness of our current antibiotics, we urgently need to expand the range of bacterial processes that medicines can target.
Rather than focusing on the cellular targets used by many existing antibiotics, the researchers investigated the methylerythritol phosphate, or MEP, pathway, which is a series of reactions that Acinetobacter baumannii and Klebsiella pneumoniae use to produce compounds essential for survival. Their work centered on IspC, an enzyme that controls an early, committed step in this pathway. Human cells make the same essential building blocks through a different pathway and do not contain IspC, making the bacterial enzyme an appealing starting point for developing antibiotics that selectively disrupt bacterial growth while minimizing effects on human cells.
Using a naturally occurring molecule called fosmidomycin as a starting point, the team designed and tested dozens of modified versions in search of compounds that could do a better job stopping bacterial growth. Scientists have long known that fosmidomycin can interfere with this bacterial process, but it has limitations that make it less useful as a medicine. The researchers hoped that reengineering the molecule would produce stronger, more effective candidates.
Their search yielded several promising results. Two compounds stood out for their ability to shut down the bacterial target in laboratory tests, while others showed improved performance against live cultures of Acinetobacter baumannii, a pathogen known for its resistance to many antibiotics.
George Mason students played a key role throughout the project, contributing to laboratory experiments, data analysis, and structural biology studies.
"The Mason students were active members of the research team, not simply observers. They produced and purified the bacterial enzymes, carried out the enzyme-inhibition studies and antibacterial testing, analyzed the resulting data, and established and optimized the experimental conditions required to obtain high-resolution protein crystal structures,” Couch explained.“ Their work was central to connecting the chemistry, biochemistry, microbiology, and structural biology components of the project, and it contributed directly to both the scientific conclusions and the peer-reviewed publication."
Couch said the project also highlights the opportunities George Mason students have to participate in research that addresses major global challenges.
"Antibiotic resistance is a global health challenge, and our students had the opportunity to work alongside faculty scientists and external collaborators on research aimed at developing entirely new therapeutic approaches."
The team also developed modified compounds known as "prodrugs," which are designed to enter bacterial cells more easily before converting into their active form. One of these candidates demonstrated particularly strong activity against multiple clinical strains of A. baumannii, suggesting a potential path toward more effective treatments.
While the compounds are still in the research stage and require further testing, the findings suggest the approach could help advance the search for new antibiotics at a time when drug-resistant infections are becoming an increasingly urgent global health challenge.
The findings represent another step toward developing new tools to address antibiotic resistance, an area where the need for innovation continues to grow worldwide. As drug-resistant bacteria evolve faster than the antibiotic pipeline can replace existing treatments, research efforts like this one may help identify entirely new ways to combat infection.
"I am delighted that our work was selected for the cover of ACS Infectious Diseases. Proof that if we invest in Mason students, they will put Mason research on the world stage,” Couch said.
