Molecular weapon targets bad bacteria

January 12, 2018 by Adela Talbot, University of Western Ontario

Instead of prescribing a broad-spectrum antibiotic, like a tiny nuclear missile that indiscriminately kills both bad and good bacteria, Greg Gloor is working on developing a targeted molecular weapon that will combat only the body's most detrimental, infectious invaders.

"We want to be able to modify the microbiome in very precise ways. Your microbiome is the bacteria that live on and around you, and it has a dramatic influence on your health and overall well-being," said Gloor, a professor of Biochemistry at the Schulich School of Medicine & Dentistry.

The microbiome is made up of that support your health and immune system, he said, and when bad bacteria invade, doctors generally prescribe antibiotics that kill both good and bad strains. Killing both strains can cause problems, such as an imbalance in that leads to poor digestive health. What's more, with the widespread use of antibiotics, the bad bacteria that doctors want to eradicate are increasingly becoming resistant to treatment.

Gloor, together with a team of researchers at Western, McMaster and Guelph universities, is working to address this problem by developing what he calls a "highly targeted nuclear warhead" molecule to modify an individual's microbiome and hone in on eradicating only bad bacteria, when they invade. The project, Microbiota Modulation with a Hybrid CRISPR Nuclease, is one of five supported by the Weston Family Microbiome Initiative, which provides research funding for high-impact projects seeking to develop novel microbiome-based therapies and provide proof-of-principle evidence for longer-term initiatives.

"There are good tie-ins between the bacteria in your gut and your neurological state. They can modulate mood; they can respond to mood; there's a two-way communication. They are absolutely required for the proper development of the immune system," Gloor noted.

"We want to get rid of the bad bacteria that does not contribute to a healthy immune system. We know that antibiotics are becoming less and less effective and we, along with probably 100 other groups around the world, are trying to figure out ways to modulate microbiomes in very precise ways to target (bad bacteria)."

Our ability to change the composition of the microbiome is limited, he explained. Because antibiotics kill good and bad bacteria alike, medical intervention compromises the microbiome. Gloor's project aims to provide controlled and precise manipulation of the microbiome by using CRISPR gene editing technology, which allows genetic material to be added, removed or altered at particular locations in the genome, including that of bacteria. Altering the with a hybrid CRISPR molecule would eradicate and only target pathogens – the bad bacteria – while slowing the growth of the bacterial population and help the body reach a healthy equilibrium.

"We are going to produce what we call a highly targeted warhead molecule. We can use the CRISPR (nucleus), attached to another nucleus, to make it more specific and more effective. We are going to take this hybrid, dual nuclease to target any bacteria that we choose inside the gut, like, for example, C. difficile," Gloor said.

"There are lots of very useful members of the clostridium genus but C. difficile is not among them. But if we can superficially target C. difficile, but leave the beneficial clostridia, that is ideal. Rather than basically throwing a nuclear warhead into your gut and walking away, you go in with an assassin or a sniper and pick off the C. difficile."

Working with Biochemistry professors David Edgell and Bogumil Karas, Gloor's team is using a different delivery mechanism than most to target bad bacteria with a hybrid CRISPR molecule. They are using conjugated plasma, just one of the mechanisms bacteria use to exchange genes. The plasma can infect large swaths of bacteria in the gut. Edgell and his colleagues are allowing it first to transfect the entire bacterial population, then activating it to specific bacteria whose DNA will be destroyed by the hybrid molecule. After this process is complete, the plasma would self-destruct.

"We are making a very complicated system that mimics your gut. Practically speaking, this is really precision medicine, where you know what the cause of the condition is, whether that is C. difficile, or tuberculosis or Legionnaire's or meningitis, you first identify the actual sequence of the organism causing it, then you target that. You produce a vector specific to the bacteria that targets those specifically, and you inject it," Gloor said.

"We envision that our CRISPR plasmid would be well-suited to chronic bacterial infections that are difficult to access with other types of antimicrobial agents," Edgell added.

But the potential benefits of this project extend beyond precision medicine, Gloor said.

When companies make yogurts and fermented foods, which contain good bacteria, manufacturers are constantly fighting contamination. A hybrid CRISPR molecule could prevent infection of the good bacterial cultures.

Environmental cleanup could benefit, as well, Gloor said.

"Quite often, if you want to clean up an environmental site, you want to grow particular bacteria that can degrade a petrochemical. You inject activated carbon, which binds up the petrochemical and then inject fertilizer – nitrogen sulfur – to allow the good bacteria to grow. But bacteria that don't degrade (will) overgrow. Ideally, you want to have the bacteria that can degrade the hydrocarbon be able to fight off the other bacteria that just want to use the fertilizer nutrients. With (a hybrid CRISPR molecule), you can accelerate the decontamination of sites," Gloor said.

"At any time, in any situation where there are more than two in the system—where one is beneficial, doing something in the health or industrial process, and the other one isn't—then you can target the bad one and reduce its numbers and allow the beneficial one to take over. That's our plan."

Explore further: How the microbiome could tackle antibiotic resistant infections in the lungs

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