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Societal Relevance and Literature Pertinent to the Proposal

GT toxins are important virulence factors in various pathogenic organisms responsible for a number of diseases and epidemics.

Infections by the pathogen Clostridium difficile (C. diffilcile) are the leading cause of nosocomical antibiotic-associated diarrhea (AAD) in industrialised countries and it typically affects people who have previously received antibiotic treatment. In fact, surveillance performed by Statens Serum Institut (SSI) in 2008 confirmed several outbreaks of C. difficile infections in Denmark which was caused by the epidemic hypervirulent CD027 strain associated with increased virulence probably due to higher amounts of toxin production. In 2009 SSI reported 596 confirmed cases of infections by CD027 and in 2010 the number had increased dramatically to 825 cases. In the U.S.A. alone, the annual incidence of AAD are more than three million cases. In addition, diarrhea caused by the enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) strains are an emerging problem and is associated with significant morbidity and mortality in humans. Importantly, there is no antibiotic treatment of EHEC infections in infants because of a severe risk of acute kidney failure. Not all the virulence factors from these pathogens are known. Therefore, identifying and understanding the basic function of the toxins in mediating infection tropism and pathogenesis is an important future research goal. While the media clamors for new antibiotics, the growing bacterial drug resistance has dampened the enthusiasm of large pharmaceutical companies in their pursuit of alternative antibacterials. Alarmingly, the pipeline for developing new therapeutics consists mainly of new versions of a small core of antibiotics including β-lactams, quinolones, macrolides and glycopeptides. An alternative strategy to combat infection is to neutralise the virulence factors by small molecule therapy, thereby helping to disarm the offending microbe. Furthermore, antivirulence compounds offer two significant advantages over conventional antibiotics: Firstly, these inhibitors are directed towards specific mechanisms (targets) in the offending pathogen that promote infection rather than against an essential metabolic factor in the pathogen. Disarming microorganisms of their virulence properties without threatening their survival offers reduced selection pressure, making it less likely to induce drug-resistant mutations. Secondly, virulence-specific therapeutics avoids the undesirable effects on the host microbiota that are associated with current antibiotics.

Last revised 15 November 2016

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