Looking for weaknesses in difficult difficile

C. difficile genome highlights the many weapons of this most awkward pathogen

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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 in a report in Nature Genetics.

C. difficile 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. C. difficile is now more prevalent and causes a greater mortality than the notorious superbug MRSA.

The research shows that half of genes found in C. difficile 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 C. difficile strains are highly variable. Most important, and unlike its nearest relatives, C. difficile 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”.

C. difficile can thrive when patients are given wide-spectrum antibiotics, which wipe out protective gut bacteria, allowing C. difficile 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 C. difficile is in a state of flux. More than 10 per cent of the C. difficile 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.”

Dr Mohammed Sebaihiawho led the genome analysis at the Wellcome Trust Sanger Institute

C. difficile 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 C. difficile spores. Because spores are highly resistant to most disinfection methods, C. difficile 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.

C. difficile 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 C. difficile 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.

“When we compared eight different strains of C. difficile we were surprised to find that the species is actually a ‘zoo’ of strains. Only 40 per cent of the genes are shared between them. More than 10 per cent 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 C. difficile ticks and help to explain how the hypervirulent strains emerged and spread so rapidly.”

Professor Brendan Wren from the London School of Hygiene & Tropical Medicine

The genome also yielded a wealth of information about how C. difficile can prosper in the gut. For example, it produces a chemical called paracresol, which kills other bacteria: as a result, when C. difficile 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 per cent of children less than two years of age carry C. difficile with no apparent symptoms. Previous research suggests that C. difficile 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.

More information

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

Websites

Publications:

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Selected websites

  • 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.

  • 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.