Bacteria rely on a host of different virulence factors to colonize the host and create pathogenesis. For some infections, therapeutic strategies targeting virulence factors such as toxins or adhesins have the advantage of not putting selective pressure on the organism, and thereby avoiding resistance problems. In recent years, the precise mechanism of pathogenesis and the crucial virulence factor for colonization of several important infections has been uncovered. This understanding provides fertile grounds for chemists to devise innovative strategies to prevent pathogenesis.
Clostridium difficile is a so-called “superbug” that is the cause of serious infections, especially in hospitalized patients. When the healthy gut flora of a patient is depleted, C. difficile can colonize the colon and cause a series of life-threatening diseases. Recently, emerging hypervirulent strains of C. difficile are causing more frequent and severe diseases. The current treatment for severe C. difficile infection (CDI) is vancomycin, but is plagued by high relapse rates and the threat of resistance against this last-resort antibiotic. A newly approved antibiotic for CDI, fidaxomicin, does not improve relapse rates in common hypervirulent strains. Therefore, there is a need for new therapy that would ideally not put selective pressure on the bacteria. Two toxins (TcdA, TcdB) secreted by the bacteria in the colon are responsible for the pathogenesis. Thus, there is an opportunity to manage the disease by targeting the toxins in the colon rather than killing the bacteria.
TcdA and TcdB are closely related large multi-domain proteins. The “warhead” of the toxin is a glucosyltransferase that inactivates important proteins in the cell cytosol. The remainder of the toxin is responsible for cell-binding, translocation and auto-processing, and is essential for the glucosyltransferase to reach the cytosol.
In this project we aim at interfering with the uptake mechanism of the "warhead" by using small molecules. This research could provide an important therapeutic alternative to antibiotics that would not be susceptible to resistance problems.