Northeastern University was awarded a $2.7 million grant by the National Institutes of Health to help develop a targeted therapy to combat a contagious and potentially lethal bacterial pathogen commonly found in hospital and nursing home settings called Clostridium difficile (C. difficile). The five-year international project, led by Northeastern’s Antimicrobial Center under the direction of professor Kim Lewis, Ph.D., aims to create a combination therapy method for humans by disabling the resistance mechanisms for the natural antimicrobial berberine.
“Our goal is to emulate a natural occurring process in plants that kills bacterial infections in humans so that we can more effectively treat people infected by this pathogen,” said Lewis.
Infection from C. difficile is a rising health problem, affecting more than 250,000 Americans a year. Found in the human intestine in small amounts, C. difficile can overgrow in response to antibiotics resulting in severe intestinal discomfort, colitis, and even death, underscoring the need for effective treatments.
Previous research in plants has shown that berberine, a principal component of the plant Goldenseal, has limited antimicrobial activity because Multi-drug Resistant pumps (MDRp) immediately pump berberine out of the cell. This is the only known resistance mechanism against berberine. When MDRp inhibitors are present, however, the activity of berberine against gram-positive bacteria, like C. difficile, increases by 60-fold. Hence this combination of MDR efflux inhibitors and berberine results in a powerful antimicrobial agent capable of eradicating C. difficile.
“Many current antimicrobial agents fail because bacteria can develop a resistance to the agent,” said Lewis. “Given the amount of compounds that we can use to develop different MDR inhibitors, our method will help us stay ahead of the pathogen resistance.”
Current treatment methods are only effective against growing bacteria, whereas this combination method would prevent stationary C. difficile cells from forming spores, preventing a relapse.
In addition, MDR inhibitors have a high probability of being identified in compound libraries, creating an opportunity to rationally manage drug resistance.
In order to eliminate compounds that could be toxic and not function in vivo, the team will use a previously established model to rapidly identify the right compounds to pump into their drug development pipeline.
This project will be done in collaboration with Fred Ausubel, professor of genetics at Harvard Medical School and molecular biologist at Massachusetts General Hospital, and John Bremner, professor of chemistry at the University of Wollongong in Australia.