Clemson chemist gets $1.7 million grant to develop tools for understanding how human gut bacteria work

A National Institutes of Health grant could help Clemson University researchers understand important metabolic processes used by a group of bacteria that has been connected with Type 1 diabetes and colon cancer.

That understanding could eventually lead to therapies that inhibit the bacteria's ability to cause disease.

Daniel Whitehead, associate chair of the Department of Chemistry, will receive $1.7 million over five years for research that focuses on two areas - developing new chemical tools to better understanding how certain gut microbes metabolize dietary polysaccharides and to develop new synthetic chemistry strategies to make rare, biologically active chemical compounds called heterocycles.

Bacteroides species are common gut bacteria which have been associated with some metabolic disorders and have evolved a complex set of enzymes that they use to recognize dietary polysaccharides and break them down for energy. While much work has been done to characterize these enzyme suites, fundamental questions remain about the suitability of this system as a potential target for drug molecules to influence human disease.

Virulence factors

"Pathogenic bacteria use a variety of behaviors, called virulence factors, that help them cause disease, and we want to understand how disrupting this major metabolic pathway might affect these factors," Whitehead said.

While researchers know a lot about the pathway itself, they don't know as much about how the operation of that pathway influences other factors in the bacteria that promote disease, he said.

"What we have the ability to do with this grant is think about developing selective chemical tools that allow us to shut down that pathway to see how that affects their ability to maintain virulence," Whitehead said.

Whitehead said his lab will examine how the influence of the pathway affects the bacteria's antibiotic resistance. This work is also enabled by active collaborations with Kristi Whitehead, a microbiologist in the Department of Biological Sciences, and Brian Dominy, a computational biophysical chemist.

The team will evaluate the influence of polysaccharide metabolism on virulence factors that include antibiotic resistance, biofilm formation (a layer of bacteria adhered to a surface) and the expression of a protein-based toxin.

Disrupting the pathways

Scientists know that these bacteria form biofilms but the question is are they able to form and maintain those when this particular metabolic pathway is disrupted.

"We know that when they make biofilms, they up regulate this pathway. Now, we can actually prevent them from doing that with a small molecule to see whether or not their ability to grow and maintain biofilms is diminished," said Whitehead. The formation of biofilms and toxin expression are both important factors influencing this bacteria's promotion of colon cancer.

If changes in the ability of the bacteria to exhibit virulence factors are observed when the pathway is disrupted, it would suggest that the pathway may be a reasonable therapeutic target to treat or prevent disease. But Whitehead said the research could, more importantly, provide a deeper understanding of how the entire system functions.

"When you have an inhibitor which shuts down the pathway, we don't necessarily understand exactly which enzyme we're inhibiting. It could be a number of them. It could influence the ability of the bacteria to even express the system itself. It could have downstream effects on other enzyme suites that also target other complex carbohydrates," he said, "so the fact that we can develop chemical probes now allows us to understand all of these different factors on a deeper level. That fundamental understanding is probably more immediately important than demonstrating that the pathways may be a viable therapeutic target."

Rare compounds

The second part of the grant focuses on developing new reactions to make chemicals, specifically a subclass of organic chemicals called heterocycles - organic compounds that contain rings of carbon along with one or more heteroatoms, which include oxygen, nitrogen and sulfur. Heterocycles are useful for developing new drugs, Whitehead said.

Whitehead's lab is concentrating on an exceptionally rare class of heterocycles called diazacyclobutenes.

When his lab started working on them in 2018, only 11 known examples of this class of compounds existed. Whitehead's lab has made more than 200 of them. Working with James Morris in Clemson Eukaryotic Pathogens Innovation Center, the lab has demonstrated that some of these compounds have biological properties and can kill parasites in a selective way.

"We don't yet understand why they kill parasites. We don't know the mechanism of action. We just know they kill them but do not harm human cells," he said. "Now, we want to understand why they have this effect on parasites. We're able to study that for the first time because we're really the only people in the world that are making these types of compounds right now or developing tactics to make those kinds of molecules. We're enabling, for the first time, access to a class of compounds that were otherwise not well studied. We've filled in a synthetic gap."

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