25th June 2006


Looking for weaknesses in difficult difficile

Cdiff genome highlights the many weapons of this most awkward pathogen

Micrograph depicts Gram-positive C. difficile bacteria

The emergence of 'superbugs' - bacteria resistant to several antibiotics - is a major problem facing health-care providers worldwide. Today, a team of scientists led by the Wellcome Trust Sanger Institute detail the genome of the multiply-antibiotic-resistant Clostridium difficile (Cdiff) in a report in Nature Genetics.

Cdiff is the leading cause of hospital-acquired infections in the developed world and caused more than 44,000 cases of disease (mostly in the over-65s) in the UK in 2004. Cdiff is now more prevalent and causes a greater mortality than the notorious superbug MRSA.

The research shows that half of genes found in Cdiff are absent from four of its bacterial cousins (the species that cause botulism, gas gangrene and tetanus and a harmless species, Clostridium acetobutylicum), and that even Cdiff strains are highly variable. Most important, and unlike its nearest relatives, Cdiff can readily exchange genes and resistance elements. The team emphasizes that this research "serves as a timely reminder on restricting the use of antibiotics given orally".

" More than 10% of the Cdiff genome consists of mobile elements - sequences that can move from one organism to another - and this is how it has acquired genes that make it such an effective pathogen "

Dr Mohammed Sebaihia

Cdiff can thrive when patients are given wide-spectrum antibiotics, which wipe out protective gut bacteria, allowing Cdiff to multiply and release its toxins. It causes a range of diseases from antibiotic-associated diarrhoea to a life-threatening colon disease, called pseudomembranous colitis.

"The genome of Cdiff is in a state of flux," commented Dr Mohammed Sebaihia, who led the genome analysis at the Wellcome Trust Sanger Institute. "More than 10% of the Cdiff genome consists of mobile elements - sequences that can move from one organism to another - and this is how it has acquired genes that make it such an effective pathogen."

"It has gained an array of genes that make it resist antibiotics, help it to interact with, and thrive in, the human gut and help it to change its surface. This combination gives it a hugely impressive range of resources to help it prosper in humans."

Cdiff is an anaerobe - it thrives in the absence of oxygen - and can 'hibernate' in adverse conditions by forming spores. It is thought that people are most commonly infected by picking up Cdiff spores. Because spores are highly resistant to most disinfection methods, Cdiff is very difficult to eradicate and can easily spread among patients.

Since 2003, a new and more virulent strain (called NAP1/027) has emerged in hospitals in North America which has resulted in increased mortality rates. This strain is now present in most UK hospitals, partly explaining the increased prevalence and mortality.

Cdiff is resistant to several antibiotics and is treatable with only two antibiotics, metronidazole and vancomycin. However, there are well-founded fears that it may become resistant to these.

With increased rates of infection, the results could not be timelier, suggested Professor Julian Parkhill, Head of the Pathogen Sequencing Unit at the Wellcome Trust Sanger Institute: "Clostridium difficile is so called because it is a difficult organism. It is not only resistant to disinfection and antibiotics, it has been resistant to research. It is very difficult to grow and despite previous painstaking genetic work, it has yielded information only reluctantly. The genome sequence reveals the full gene repertoire of this pathogen, and the information gleaned from it will provide the basis for future studies."

Because Cdiff is difficult to grow and to study in the lab many of the discoveries emanating from the genome sequence are completely novel and will provide insights into the mechanisms by which the organism causes disease, help in the development of new strategies to detect and prevent infections and may ultimately lead to new treatments.

But the story is far from a simple one, as Professor Brendan Wren from the London School of Hygiene & Tropical Medicine, explained: "When we compared eight different strains of Cdiff we were surprised to find that the species is actually a 'zoo' of strains. Only 40% of the genes are shared between them. More than 10% of its genome is derived from self-mobile DNA elements and its overall variation is remarkable. The genetic comparison of these strains will help us understand how Cdiff ticks and help to explain how the hypervirulent strains emerged and spread so rapidly."

The genome also yielded a wealth of information about how Cdiff can prosper in the gut. For example, it produces a chemical called paracresol, which kills other bacteria: as a result, when Cdiff sees an opening, it can kill its competitors and can take over more rapidly. In addition, it can survive bile acids in the gut, which kill many bacteria, by pumping out this toxic substance. Amazingly, perhaps 50% of children less than two years of age carry Cdiff with no apparent symptoms. Previous research suggests that Cdiff cannot attack their gut cells, perhaps because infants have not yet developed a 'receptor' that the bug uses as part of its pathogenic attack.

The availability of the genome may help in the development of more accurate diagnostic tools, provide information about drug resistance and help to track emergence of new, more virulent strains. The wealth of sequence information also exposes new sites against which new treatments or vaccines might be targeted.

Notes to Editors

Publication details

  • The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome.

    Sebaihia M, Wren BW, Mullany P, Fairweather NF, Minton N, Stabler R, Thomson NR, Roberts AP, Cerdeño-Tárraga AM, Wang H, Holden MT, Wright A, Churcher C, Quail MA, Baker S, Bason N, Brooks K, Chillingworth T, Cronin A, Davis P, Dowd L, Fraser A, Feltwell T, Hance Z, Holroyd S, Jagels K, Moule S, Mungall K, Price C, Rabbinowitsch E, Sharp S, Simmonds M, Stevens K, Unwin L, Whithead S, Dupuy B, Dougan G, Barrell B and Parkhill J

    Nature genetics 2006;38;7;779-86

Funding

  • This work was funded by the Wellcome Trust
  • Participating Centres

    • Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinton, Cambridge, CB10 1SA, UK
    • Department of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK
    • Eastman Dental Institute for Oral Health Care Sciences, University College London, 256 Gary's Inn Road, London WC1X 8LD, UK
    • Centre for Molecular Microbiology and Infection, Imperial College London, London, SW7 2AZ, UK
    • Centre for Biomolecular Sciences, Institute of Infection, Immunity and Inflammation, University of Nottingham, University Park, Nottingham NG7 2RD, UK
    • Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, Paris, France

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The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

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The Wellcome Trust and Its Founder

The Wellcome Trust is the most diverse biomedical research charity in the world, spending about £450 million every year both in the UK and internationally to support and promote research that will improve the health of humans and animals. The Trust was established under the will of Sir Henry Wellcome, and is funded from a private endowment, which is managed with long-term stability and growth in mind.

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