Novel anti infectives for Clostridium difficile infection

SUMMARY Clostridium difficile infection CDI is now the countryandapos s leading cause of antibiotic associated diarrhea and has increased acute care facility costs by $ billion per year CDI was originally restricted to health care settings but is now responsible for community acquired infections as well The infection toll is now approaching cases per year leading to andgt fatalities It has clearly become urgent to find novel ways of preventing and treating infection In fact the US Department of Health and Human Services has set a goal of reducing hospitalization due to C difficile infection CDI by by In most cases the onset of CDI is due to treatment of a patient with a broad spectrum antibiotic a treatment that undercuts the protective effect of the normal microbial flora Unfortunately the standard treatment for CDI also depends on antibiotics all of which leave a significant number of patients uncured Moreover of patients who appear to have been cured suffer one or more cases of recurrent infection The recurrence is undoubtedly due to the fact that the antibiotics used to treat CDI do not allow the microbiota to re establish itself in a timely and efficient manner Novel non antibiotic anti infective approaches are clearly needed to reduce the impact of CDI The form of C difficile that initiates infection is the spore Since C difficile virulence factors are produced by vegetative cells germination of the spore and its return to vegetative growth is the first step in pathogenesis Importantly spore germination depends on certain human bile acids and is inhibited by others In healthy people the microbiota eliminates the most active pro germination bile acids and produces the bile acids most effective in blocking germination and vegetative cell growth We have synthesized analogs of both activating and inhibitory bile acids and identified lead compounds that block spore germination in vitro andgt times more efficiently than does the most inhibitory natural bile acid We propose here to synthesize a further set of compounds that are designed to maintain germination inhibition while reducing the likelihood of metabolism absorption and toxicity We will test the ability of these compounds to prevent germination both in vitro and in vivo and to resist metabolism by the gut flora The new lead compounds will then be tested for their basic pharmacokinetics and potential toxicity in mice and for their ability to inhibit primary and recurrent infection The new lead compounds created in this nine month project will subsequently be tested in animals for more detailed pharmacokinetics as a means of preparing them for IND approval and a Phase I clinical trial NARRATIVE Clostridium difficile is now the most common cause of antibiotic associated diarrhea in the US and the most frequent cause of healthcare acquired infections No preventive mechanisms exist and current treatments depend on antibiotics that make patients susceptible to recurrent infection by preventing the re establishment of a protective microbial community in the intestine This proposal aims to develop for clinical use a set of novel anti infectives that specifically block the conversion of C difficile spores to growing cells and thereby inhibit infection without inhibiting the growth of protective microbes in the intestinal tract