Invention Summary
The invention is a prophylactic approach to preventing Clostridium difficile-associated diseases (CDAD) or Clostridium difficile infection (CDI). Clostridium difficile is a bacterium that causes diarrhea and more serious intestinal conditions. The method involves administering to a mammalian subject an effective amount of a germination-inhibiting compound derived from taurocholate. Germination of a spore, such as Clostridium difficile, is the process in which a spore begins to grow into vegetative cells, and sporeling hyphae. Bacterial spores (endospores) are dormant, non-reproductive structures formed by bacteria in response to environmental stress. Once environmental conditions become favorable, the spores germinate and the bacteria proliferate. In the case of pathogenic bacteria, germination in a human host may result in disease.
Market Opportunity
Clostridium difficile causes Clostridium difficile-associated diseases (CDAD) and there has been a ten-fold increase in the number of cases within the last 10 years, with hyper-virulent and drug resistant strains now becoming endemic. Perhaps most worrying are the cases of CDAD now being reported with no underlying antibiotic use. Alternative therapies—used as stand-alone agents or in conjunction with antibacterials—are aimed at trying to re-establish the native gut microorganism population, reducing the levels of Clostridium difficile toxins, or stimulating the immune system. The pressing need for new and effective agents to treat Clostridium difficile is particularly acute because of its refractory nature to many broad spectrum antibiotics (including β-lactam and quinolone antibiotics) and the frequency with which resistance emerges. Current therapies are extremely limited; nearly all antibiotic classes are associated with causing the disease. This inability to control spore formation allows for continued contamination of the hospital environment. As such, agents able to eradicate vegetative cells and control endospores would be of significant advantage.
Features & Benefits
•Clostridium difficile spores bind the germinants taurocholate (a bile salt) and glycine through a complex mechanism. A synthetic taurocholate analog with an m-aminobenzenesulfonic acid side chain (CamSA) is an efficient inhibitor of Clostridium difficile spore germination. CamSA binds to Clostridium difficile spores approximately 1,000-fold better than the natural taurocholate germinant. CamSA does not show acute toxicity even at 300 mg/Kg and is stable to the GI tract environment.
•Clostridium difficile spores revert to toxin-producing bacteria in nutrient-rich environments. Compounds able to curtail spore germination could also prevent Clostridium difficile infection. Anti-germination compounds could be used to supplement antibiotic treatments of hospitalized patients. Once the antibiotic regime is completed, re-establishment of the normal gut flora will prevent Clostridium difficile colonization and anti-germination therapy can also be stopped.
Intellectual Property Published Patent: US-2014-0045808-A1