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Innovations in the Battle Against AMR: MIT Researchers Develop Engineered Bacteria to Protect “Good” Gut Microbes

While antibiotics are life-saving drugs, they are also able to harm the beneficial microbes that live in our gut. In fact, some patients who receive antibiotic treatment can develop inflammation or opportunistic infections like Clostridiodes difficile (C. difficile). Additionally, indiscriminate use of antibiotics on gut microbes can lead to the spread of resistance to the drugs.

To figure a way to reduce these risks and protect the nature of the human digestive tract, a group of MIT engineers took a strain of bacteria that is safe for human consumption and engineered it to produce an enzyme that breaks down a class of antibiotics called beta-lactams, which include ampicillin, amoxicillin, and other commonly used drugs. When the “living biotherapeutic” was administered with antibiotics to lab mice, it protected the microbiota in the gut, but also allowed levels of antibiotics in the bloodstream to remain high.

When delivered orally, the bacteria populate intestines and secrete the enzyme beta-lactamase, which breaks down antibiotics that reach the intestinal tract. This method could also be used in conjunction with antibiotics that are injected because they also reach the intestine. Once their mission is complete, the engineered bacteria leaves the body through the digestive tract.

Thus, this research shows that synthetic biology can be utilised to create a new class of engineered therapeutics to reduce the adverse effects of antibiotics.

Our Guts Need Protection

For the past 20 years, research has revealed that microbes in the human gut play pivotal roles in our bodies, not just in metabolism, but also in immune function and the nervous system. To accomplish these functions, they assemble into a highly diverse community. Issues with these functions arise when medications or particular diets affect the composition of microbiota and create an altered state known as dysbiosis. Some microbial groups disappear, while others see an increase in metabolic activity, which causes an imbalance that may lead to health problems.

An example would be the infection of C.difficile, a microbe that is common in the gut but not harmful. However, when antibiotics kill off competing strains, C. difficile can take over and subsequently cause diarrhoea and colitis. It is an affliction that infects roughly 500,000 people in the US every year, and causes an estimated 15,000 deaths annually.

In order to combat the adverse effects of antibiotics, some doctors do prescribe probiotics; unfortunately, these are also usually susceptible to antibiotics and cannot fully replicate the original microbiota in the gut.

As such, the biocontainment strategy worked on by the MIT engineers is advantageous, as it enables the delivery of antibiotic-degrading enzymes to the gut without causing horizontal gene transfer or adding a competitive advantage to the live biotherapeutic.

Ensuring Microbial Diversity

To test out their theory, researchers gave selected lab mice two oral doses of engineered bacteria for one injection of ampicillin. In the gut, these mice had the same levels of ampicillin circulating in their bloodstream as other mice who were not given the engineered bacteria. However, they also maintained a much higher level of microbial diversity. In addition, none of them developed opportunistic C.difficile infections. The findings strongly indicate that this approach can protect gut microbiota and preserve the efficacy of antibiotics.

The team also discovered that elimination of the evolutionary pressure of antibiotic treatment made it significantly more unlikely that microbes in the gut would develop antibiotic resistance after treatment. Their next step is to develop a version that can be tested in people with a high risk of developing acute diseases as a result of antibiotic-induce dysbiosis and they are hoping that it could eventually protect anyone who requires antibiotics for infections outside the gut.

With this new technology, antibiotics will be made safer by preserving beneficial gut microbes and reducing the possibility of new antibiotic resistant variants emerging.