High-throughput analysis of gene essentiality and sporulation in Clostridium difficile
Open accessAbstract
UNLABELLED: Clostridium difficile is the most common cause of antibiotic-associated intestinal infections and a significant cause of morbidity and mortality. Infection with C. difficile requires disruption of the intestinal microbiota, most commonly by antibiotic usage. Therapeutic intervention largely relies on a small number of broad-spectrum antibiotics, which further exacerbate intestinal dysbiosis and leave the patient acutely sensitive to reinfection. Development of novel targeted therapeutic interventions will require a detailed knowledge of essential cellular processes, which represent attractive targets, and species-specific processes, such as bacterial sporulation. Our knowledge of the genetic basis of C. difficile infection has been hampered by a lack of genetic tools, although recent developments have made some headway in addressing this limitation. Here we describe the development of a method for rapidly generating large numbers of transposon mutants in clinically important strains of C. difficile. We validated our transposon mutagenesis approach in a model strain of C. difficile and then generated a comprehensive transposon library in the highly virulent epidemic strain R20291 (027/BI/NAP1) containing more than 70,000 unique mutants. Using transposon-directed insertion site sequencing (TraDIS), we have identified a core set of 404 essential genes, required for growth in vitro. We then applied this technique to the process of sporulation, an absolute requirement for C. difficile transmission and pathogenesis, identifying 798 genes that are likely to impact spore production. The data generated in this study will form a valuable resource for the community and inform future research on this important human pathogen. IMPORTANCE: Clostridium difficile is a common cause of potentially fatal intestinal infections in hospital patients, particularly those who have been treated with antibiotics. Our knowledge of this bacterium has been hampered by a lack of tools for dissecting the organism. We have developed a method to study the function of every gene in the bacterium simultaneously. Using this tool, we have identified a set of 404 genes that are required for growth of the bacteria in the laboratory. C. difficile also produces a highly resistant spore that can survive in the environment for a long time and is a requirement for transmission of the bacteria between patients. We have applied our genetic tool to identify all of the genes required for production of a spore. All of these genes represent attractive targets for new drugs to treat infection.
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When coupled with next generation sequencing, transposon-directed insertion site sequencing performed on C. difficile identified 404 essential genes for growth and 798 genes that are likely to affect spore production.
“When coupled with next generation sequencing, transposon-directed insertion site sequencing (TraDIS) was performed on C. difficile and identified 404 essential genes for growth and 798 genes that are likely to affect spore production (Dembek et al., 2015).”
From Gas Fermentation—A Flexible Platform for Commercial Scale Production of Low-Carbon-Fuels and Chemicals from Waste and Renewable Feedstocks (2016) · cites this paper as Dembek et al., 2015
C. difficile transposon mutagenesis identified 798 genes that are likely to affect sporulation.
“| C. difficile | Generation of more than 70,000 unique mutants via transposon mutagenesis, coupled with transposon-directed insertion site sequencing | Identification of 404 essential genes for growth; Identification of 798 genes that are likely to affect sporulation | Dembek et al., 2015 |”
From Gas Fermentation—A Flexible Platform for Commercial Scale Production of Low-Carbon-Fuels and Chemicals from Waste and Renewable Feedstocks (2016) · cites this paper as Dembek et al., 2015
C. difficile transposon mutagenesis identified 404 essential genes for growth.
“| C. difficile | Generation of more than 70,000 unique mutants via transposon mutagenesis, coupled with transposon-directed insertion site sequencing | Identification of 404 essential genes for growth; Identification of 798 genes that are likely to affect sporulation | Dembek et al., 2015 |”
From Gas Fermentation—A Flexible Platform for Commercial Scale Production of Low-Carbon-Fuels and Chemicals from Waste and Renewable Feedstocks (2016) · cites this paper as Dembek et al., 2015
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- Authors
- Dembek, M., Barquist, L., Boinett, C. J., Cain, A. K., Mayho, M., Lawley, T. D., Fairweather, N. F., & Fagan, R. P.
- Affiliations
- Imperial College London (GB)
- University of Würzburg (DE)
- Wellcome Sanger Institute (GB)
- University of Sheffield (GB)
- Corresponding author
- Fairweather, Neil F.
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2015-05
- Volume
- 6
- Issue
- 2
- Pages
- e02383-e02383
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC4358009
- OpenAlex
- W1989733081
- Cited by
- 185
- References
- 53
- Citations by year
- 2026: 14 · 2025: 12 · 2024: 18 · 2023: 19 · 2022: 14 · 2021: 19 · 2020: 17 · 2019: 20 · 2018: 15 · 2017: 18 · 2016: 14 · 2015: 5
- FWCI
- 13.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Alexander von Humboldt-Stiftung
- Wellcome Trust (098051, 089875/Z/09/A)
- Medical Research Council (098051, G0800170)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Clostridium difficile and Clostridium perfringens research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Keywords
- Clostridium difficile, gene essentiality, bacterial sporulation, transposon mutagenesis, TraDIS, transposon mutant library, antibiotic-associated diarrhea, sporulation, therapeutic target, bacterial virulence
- MeSH terms
- DNA Transposable Elements, Genes, Bacterial, Genetic Testing, Humans, Spores, Bacterial, Mutagenesis, Insertional, Clostridioides difficile, Genes, Essential, High-Throughput Screening Assays
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