The Department of Microbiology and Immunology is proud to announce that Professors David Weiss, PhD, and Craig Ellermeier, PhD, have received a new R01 grant from the National Institute of Allergy and Infectious Diseases (NIAID) to investigate a novel class of enzymes critical to the survival of Clostridioides difficile—a major cause of hospital-acquired infections.

C. difficile is a leading cause of infectious diarrhea in healthcare settings and has been designated an urgent public health threat by the CDC. While the antibiotic vancomycin is effective in treating C. difficile, it also disrupts the healthy gut microbiota, often leading to relapse after treatment ends.

Weiss and Ellermeier’s research focuses on a unique vulnerability in C. difficile: the enzymes that crosslink its peptidoglycan (PG) cell wall. Unlike most bacteria, which rely on 4-3 crosslinks formed by PBPs, C. difficile depends on 3-3 crosslinks formed by L,D-transpeptidases (LDTs). Their team recently discovered that these 3-3 crosslinks are essential for C. difficile’s survival, making it the first known organism to require them.

Importantly, they have identified a new family of LDTs containing a VanW catalytic domain. This discovery opens the door to developing narrow-spectrum antibiotics that target C. difficile specifically—without harming beneficial gut bacteria.

The funded project will:

• Determine the structure and catalytic mechanism of the VanW domain;
• Investigate how VanW-type LDTs are recruited during cell division;
• Explore the role of these enzymes in sporulation, a key factor in infection recurrence.

This research has the potential to transform how we treat C. difficile infections and contributes to the broader fight against antibiotic resistance. The department congratulates Drs. Weiss and Ellermeier on this exciting achievement and looks forward to the impact of their work.