New strategies to treat Clostridioides difficile infections: Research

MASSACHUSETTS: Researchers at Brigham and Women’s Hospital (BWH) and Massachusetts General Hospital (MGH), two of the founding institutions of Mass General Brigham, have discovered the metabolic mechanisms Clostridioides difficile uses to quickly invade the gut.

The findings point to new ways to prevent and treat the most prevalent infection types and causes of antibiotic-associated diarrhoea (HAIs). The team’s methodology has implications for comprehending more general elements of microbial metabolisms, such as antibiotic responses and the generation of significant metabolites. The findings are released in Nature Chemical Biology.

“Investigating real-time metabolism in microorganisms that only grow in environments lacking oxygen had been considered impossible,” said 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. “Here, we’ve shown it can be done to combat C. difficile infections — and with findings applicable to clinical medicine.”

“C. difficile is the leading cause of hospital-acquired infections and a leading cause of antibiotic-associated diarrhoea. Understanding its metabolic mechanisms at a cellular level may be useful for preventing and treating infections,” said 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.

C. difficile 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. difficile metabolizes nutrients while colonizing the gut could inform new approaches to prevent and treat infections.

To complete their study, Bry and Cheng, faculty in the recently formed Mass General Brigham Pathology program, used a technology called high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HRMAS NMR) 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.

The study’s findings identified new targets for small-molecule drugs to counter C. difficile colonization and infection in the gut and provide a new approach to rapidly define microbial metabolism for other applications, including antibiotic development and the production of economically and therapeutically important metabolites.