Fighting C. difficile
Clostridioides difficile is a bacterium which causes severe and potentially fatal intestinal infections. The US Centers for Disease Control and Prevention has called C. difficile one of the five most urgent resistant pathogens. C. difficile infection (CDI) is caused by the use of antibiotics because antibiotics deplete the gut microbiota that normally protects against CDI. As a result, current antibiotic treatments plague patients with disease recurrence. Therefore, novel therapies are urgently needed to deal with CDI. The pathogenesis of C. difficile is driven by two large protein toxins: TcdA and TcdB, the latter being the primary virulence determinant in human infections. Targeting TcdB is an attractive therapeutic approach since it avoids the use of antibiotics. We have recently published an innovative approach using small molecules to inactivate TcdB (Ivarsson et al. Cell Chemical Biology 2019). We hypothesized that analogues of inositol hexakisphosphate (IP6), a natural co-factor responsible for TcdB auto-processing inside human intestinal cells, would be able to pre-emptively induce auto-processing in the gut lumen, prior to toxin cell uptake. We synthesized IT2S4, an inositol phosphate analogue, which effectively induced toxin cleavage in the presence of intestinal concentrations of calcium. Gratifyingly, IT2S4 reduced mortality in a fulminant mouse CDI model when administered orally. This proof-of-principle was the first demonstration that auto-processing of a toxin can be exploited for therapeutic purposes. We are currently designing and evaluating second-generation inositol phosphate analogues and further gaining insight into the in vivo mechanism of action of our molecules.
Targeting the Gut Microbiota
The human gut microbiota is essential to our physiology and has recently been linked to many conditions, including obesity, inflammatory bowel diseases, and even neurodegenerative diseases. Very recently, the gut microbiota has been convincingly implicated in the efficacy of immune-checkpoint inhibitors (ICIs) in cancer. Immunotherapy that targets immune checkpoints like programmed cell death 1 (PD-1) has revolutionized the way several cancers are treated, but a large proportion of patients do not respond to the treatment. Our colleagues have shown that non-responders had an altered microbiota, which could transfer the phenotype of treatment resistance when transplanted into germ-free mice. Importantly, the administration of immuno-stimulatory bacteria to these mice re-sensitized them to ICIs, suggesting that gut microbiota manipulations could increase cancer immunotherapy response.
Complex glycans and polysaccharides contained in our diet go through the digestive tract un-digested by the host and are a major energy source for our gut microbiota. As such, microbiota-accessible glycans are a major driver of the microbiome composition and diversity. It is therefore possible to use glycans to manipulate the composition of the gut microbiota. We aim to discover glycan prebiotics that will promote anti-tumor immunity and improve clinical response in cancer patients.