Identification of a new family of peptidoglycan transpeptidases reveals atypical crosslinking is essential for viability in Clostridioides difficile
Authors:
Kevin W. Bollinger1 , Ute Müh1 , Karl L. Ocius2 , Alexis J. Apostolos2,6, Marcos M. Pires2 4 , Richard F. Helm3 , David L. Popham4 , David S. Weiss1,5,*, and Craig D. Ellermeier1,5,*
Affiliation:
1. Department of Microbiology and Immunology Carver College of Medicine University of Iowa Iowa City, IA, USA
2. Department of Chemistry University of Virginia Charlottesville, VA, USA
3. Department of Biochemistry Virginia Tech Blacksburg, VA, USA
4. Department of Biological Sciences Virginia Tech Blacksburg, VA, USA
5. Graduate Program in Genetics University of Iowa Iowa City, IA USA
6 Present address: Haleon 1211 Sherwood Ave Richmond, VA 23220
Description:
Clostridioides difficile, the leading cause of antibiotic-associated diarrhea, relies primarily on 3-3 crosslinks created by L,D-transpeptidases (LDTs) to fortify its peptidoglycan (PG) cell wall. This is unusual, as in most bacteria the vast majority of PG crosslinks are 4-3 crosslinks, which are created by penicillin-binding proteins (PBPs). Here we report the unprecedented observation that 3-3 crosslinking is essential for viability in C. difficile. We also report the discovery of a new family of LDTs that use a VanW domain to catalyze 3-3 crosslinking rather than a YkuD domain as in all previously known LDTs. Bioinformatic analyses indicate VanW domain LDTs are less common than YkuD domain LDTs and are largely restricted to Gram-positive bacteria. Our findings suggest that LDTs might be exploited as targets for antibiotics that kill C. difficile without disrupting the intestinal microbiota that is important for keeping C. difficile in check.
Publications:
- Bollinger, Kevin W.; Müh, Ute; Ocius, Karl L.; Apostolos, Alexis J.; Pires, Marcos M.; Helm, Richard F.; Popham, David L.; Weiss, David S.; Ellermeier, Craig D.; Identification of a new family of peptidoglycan transpeptidases reveals atypical crosslinking is essential for viability in Clostridioides difficile; bioRxiv, 2024
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| File Name | File Description | File Type | File Size | File URL |
|---|---|---|---|---|
| Supp Table 1 | RNA-seq | xlsx | 235.93 KB | Login to download |
| Supp Figs 1-10 | Supp Tables 2-4 | 3.85 MB | Login to download |