The increasing incidence of primary and recurring Clostridioides difficile infections (CDI), which evade current treatment strategies, reflects the changing biology of C difficile. Here, we describe a putative plasmid-mediated mechanism potentially driving decreased sensitivity of C difficile to vancomycin treatment. We identified a broad host range transferable plasmid in a C difficile strain associated with lack of adequate response to vancomycin treatment. The transfer of this plasmid to a vancomycin-susceptible C difficile isolate decreased its susceptibility to vancomycin in vitro and resulted in more severe disease in a humanized mouse model. Our findings suggest plasmid acquisition in the gastrointestinal tract to be a possible mechanism underlying vancomycin treatment failure in patients with CDI, but further work is needed to characterize the mechanism by which plasmid genes determine vancomycin susceptibility in C difficile.
Bibliographical noteFunding Information:
Funding Grant support: NIH DK114007 and the Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
We acknowledge Lisa Till and William Moor for technical help with the mouse experiments and sample preparation, and Lyndsay Busby for secretarial assistance. We also acknowledge Scott Gamb and Trace Christen from Microscopy and Cell Analysis core in Mayo Clinic for scanning electron microscopy sample preparation as well as imaging support. The authors thank Drs Abhijit Maji and Joy Scaria from South Dakota State University for their help in C difficile RNA extraction protocol development. This work was made possible by funding from NIH DK114007 and the Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota. Minion sequencing (SAMN13638779,SAMN14824866) and RNA sequencing (SAMN14824864, SAMN14824865) files for CIM-009, and CIM-009/pX18?498 were uploaded to the National Center for Biotechnology Information. Additional data that support the findings of this study are available from the corresponding author on request. Meng Pu, PhD (Writing ? original draft: Lead). Janice M. Cho, MD (Data curation: Equal). Scott A. Cunningham, MS (Data curation: Equal). Gaurav K. Behera, Undergraduate student (Data curation: Equal). Sarah L. Becker, BS (Data curation: Equal). Talal Amjad, Medical student (Data curation: Equal). Kerryl E. Greenwood Quaintance, MS (Data curation: Equal). Helena Mendes-Soares, PhD (Data curation: Equal). Yava L. Jones-Hall, DVM, PhD (Data curation: Equal). Patricio R. Jeraldo, PhD (Data curation: Equal). Jun Chen, PhD (Data curation: Equal). Gary M. Dunny, PhD (Data curation: Equal). Robin Patel, MD (Data curation: Equal). Purna C. Kashyap, MBBS (Project administration: Lead; Writing ? review & editing: Lead). Conflict of interest Robin Patel: reports grants from ContraFect, TenNor Therapeutics Limited, Hylomorph and Shionogi. Dr. Patel is a consultant to Curetis, Specific Technologies, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, and Qvella; monies are paid to Mayo Clinic. Dr. Patel is also a consultant to Netflix. In addition, Dr. Patel has a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued. Dr. Patel receives an editor's stipend from IDSA, and honoraria from the NBME, Up-to-Date and the Infectious Diseases Board Review Course. Purna C. Kashyap: serves on the advisory board of Novome Biotechnologies and is an ad hoc consultant for Otsuka Pharmaceuticals, Pendulum Therapeutics, and IP group inc.Janice M. Cho: No conflict of interest. Scott A. Cunningham: No conflict of interest Gaurav K. Behera: No conflict of interest Sarah L. Becker: No conflict of interest Talal Amjad: No conflict of interest Kerryl E. Greenwood Quaintance: No conflict of interest Helena Mendes-Soares: No conflict of interest Yava L. Jones-Hall: No conflict of interest Patricio R. Jeraldo: No conflict of interest Jun Chen: No conflict of interest Gary M. Dunny: No conflict of interest. Funding Grant support: NIH DK114007 and the Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
© 2021 AGA Institute
- Antimicrobial Resistance
- Cell Wall Peptidoglycan
- Gram Positive
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't