Chemistry at the Human Bacteria Interface

Chemistry at the Human Bacteria Interface


Hi my name is Jason Crawford and I’m a Chemical Biologist at Yale University and my lab studies the chemistry at the human bacteria interface. Bacteria and humans have coevolved since the birth of humans and many mechanisms have been established for conflict and cooperation between humans and bacteria. What’s interesting is that bacteria
use chemistry, so small molecule metabolites, to regulate many of the interactions that they’re involved in. However if we look at the intestinal environment and we do what’s called a
metabolomics experiment, which is the basically the study of the small molecule metabolites, what’s fascinating is we find out that we actually don’t know what
very many of those molecules are. Some of those are going to be junk but others are going to be the next blockbuster signalling molecule or drug used again, to manipulate this conflict and cooperation that has evolved over many thousands of years. Current metabolomic research has focused on that small fraction of known compounds and that’s led to major generalizations about a very small minority of the metabolites in these complex populations. So my group, we decode novel metabolic pathways at that human bacteria interface. The specific sorts of signaling pathways that we look at are largely immunological in nature. It’s basically how do bacteria regulate the human immune system and vice versa. We also look at how bacterial pathways can regulate colorectal cancer initiation. Additionally certain metabolites from bacteria can affect how colorectal cancer treatment is mediated, basically establishing the efficacy of certain cancer immunotherapies. We also look at a variety of
signalling pathways as well as antibiotics. So why do we care about antibiotics from our own intestinal tract? One, they can be potentially
developed as future antibiotics for the treatment of pathogens, but those antibiotics also affect the composition of the bacteria that’s already found in our intestinal tract and disruption of this community can lead to inflammatory diseases such as Ulcerative Colitis or Crohn’s disease, exacerbation of those diseases. One specific pathway that we’ve looked at for the last six years is called the Colibactin Pathway and this pathway is found in 50 to 67 percent of human colorectal cancer patients. It’s also been shown to drive tumour formation in four different mouse models to date suggesting a pretty strong support for a causal relationship and colorectal cancer initiation. So why do we want to understand this
at the molecular level? Well we’ve spent a lot of time
looking at the structure, function and reactivity of these colibactins and by understanding that, we then discovered an enzyme that neutralizes the warhead associated with that molecule. This neutralizing agent is the first example of what we call a Cyclopropane Hydrolaze which is a member of a previously uncharacterized enzyme superfamily. We’ve also shown that that enzyme
can protect human cells when supplemented exogenously and now through
understanding that mechanism, we can now develop probiotics that secrete this enzyme in the intestine towards the development of a colorectal
cancer prophylactic.

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