Investigators see a potential new approach to therapeutic development for C diff.
A team of Mass General Brigham investigators identified metabolic strategies used by Clostridioides difficile to rapidly colonize the gut. With this discovery, the investigators believe they have identified new targets for small molecule drugs to counter C difficile colonization and infection in the gut and thus provide a new approach to rapidly define microbial metabolism for other applications, including antibiotic development and the production of economically and therapeutically important metabolites.
“Investigating real-time metabolism in microorganisms that only grow in environments lacking oxygen had been considered impossible,” co-corresponding author Lynn Bry, MD, PhD, director of the Massachusetts Host-Microbiome Center, associate medical director in Pathology at BWH, and an associate professor of Pathology at Harvard Medical School said in a statement. “Here, we’ve shown it can be done to combat C difficile infections —and with findings applicable to clinical medicine.”
C diff is an obligately anaerobic species of bacteria, which means it does not replicate in the presence of oxygen gas. C difficile causes infections by releasing toxins that allow the pathogen to obtain nutrients from damaged gut tissues. Understanding how C diff metabolizes nutrients while colonizing the gut could inform new approaches to prevent and treat infections.
The investigators used a technology called high-resolution magic angle spinning nuclear magnetic resonance spectroscopy to study real-time metabolism in living cells under anaerobic conditions. The team incorporated computational predictions to detect metabolic shifts in C difficile as nutrient availability decreased, and then developed an approach to simultaneously track carbon and nitrogen flow through anaerobe metabolism. The researchers identified how C difficile jump-starts its metabolism by fermenting amino acids before engaging pathways to ferment simple sugars such as glucose. They found that critical pathways converged on a metabolic integration point to produce the amino acid alanine to efficiently drive bacterial growth.
"Understanding its metabolic mechanisms at a cellular level may be useful for preventing and treating infections,” co–senior author Leo L. Cheng, PhD, an associate biophysicist in Pathology and Radiology at MGH and an associate professor of Radiology at Harvard Medical School, said in a statement.