Delineating the antimicrobial resistome of Clostridioides difficile

Summary

Clostridioides difficile (C. diff) is an important human pathogen, responsible for life-threatening intestinal infection in both hospital and community settings. Exacerbating the clinical impact of this organism, there is growing resistance to the antibiotics used to treat the infections it causes. Unfortunately, our understanding of the molecular mechanisms of antimicrobial resistance (AMR) in this species lags behind that for other major pathogens; whilst a number of resistance determinants have been defined to date, our knowledge of the C. diff resistome remains far from comprehensive.

This project seeks to dramatically increase our knowledge of AMR in C. diff, not only by identifying novel genetic determinants underlying resistance, but also by beginning to unravel the molecular detail of the encoded mechanisms. The potential benefits of gaining such knowledge are manifold, including building a more robust foundation for molecular AMR surveillance and providing strategic intelligence that could be exploited for producing the next generation of anti-C. diff antibiotics.

To achieve this, we will leverage access to one of Europe’s largest collections of C. diff isolates held at Leeds, which currently comprises several thousand well-characterized isolates. In the first instance, we will use bioinformatics to identify novel/potential resistance determinants in whole genome sequencing data, which will then undergo validation in molecular cloning experiments. Where such approaches are insufficient to define the genetic basis for resistance, we will use techniques such as functional metagenomics to physically ‘capture’ genes that confer AMR. Novel antibiotic resistance mechanisms will progress to structural and functional characterization, using approaches that the O’Neill lab are well versed in.

Collectively, these studies will deliver key insights into the genetic basis and mechanisms of AMR in an increasingly-important human pathogen.

References

• Wilson DN, Hauryliuk V, Atkinson GC, O'Neill AJ (2020) Target protection as a key antibiotic resistance mechanism. Nat Rev Microbiol. 18: 637-648.
• Kime L, Randall CP, Banda FI, Coll F, Wright J, Richardson J, Empel J, Parkhill J, O'Neill AJ (2019) Transient Silencing of Antibiotic Resistance by Mutation Represents a Significant Potential Source of Unanticipated Therapeutic Failure. mBio. 10: e01755-19.
• Freeman J, Vernon J, Pilling S, Morris K, Nicolson S, Shearman S, Clark E, Palacios-Fabrega JA, Wilcox M: Pan-European Longitudinal Surveillance of Antibiotic Resistance among Prevalent Clostridium difficile Ribotypes’ Study Group (2020) Five-year Pan-European, longitudinal surveillance of Clostridium difficile ribotype prevalence and antimicrobial resistance: the extended ClosER study. Eur J Clin Microbiol Infect Dis. 39: 169-177.

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