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Engineered microbe protects the gut microbiome from antibiotics

Approach protects mice from pathogenic infections and cuts down on antibiotic resistance

by Celia Henry Arnaud
April 12, 2022


Two inactive pieces of an enzyme reassemble and degrade antibiotics.
Credit: Adapted from Nat. Biomed. Eng.
An engineered microbe produces a β-lactamase as two inactive pieces that are brought together outside the cell. The reassembled enzyme degrades β-lactam antibiotics.

Broad-spectrum antibiotics attack many bacteria, including bystanders in the gut microbiome. Losing these non-pathogenic microbes can lead to an imbalance that affects gut health. Researchers have now engineered microbes to produce an enzyme that degrades β-lactam antibiotics in the guts of mice without affecting the concentration in blood. This approach protects native microbes without interfering with the antibiotic’s levels in blood. And it does so in way that minimizes the development of antibiotic resistance.

James J. Collins, a biological engineer at the Massachusetts Institute of Technology; Andrés Cubillos-Ruiz, a researcher at the Wyss Institute for Biologically Inspired Engineering; and coworkers engineered Lactococcus lactis to express an enzyme called a β-lactamase that breaks down β-lactams, a key class of antibiotics that includes penicillin and amoxicillin (Nat. Biomed. Eng. 2022, DOI: 10.1038/s41551-022-00871-9). They chose L. lactis because it’s found in food and can be safely consumed in large quantities.

β-Lactamases are usually made by gram-negative bacteria, and the enzyme stays in the space between the bacteria’s inner and outer membranes. But L. lactis is gram-positive, so it doesn’t have an outer membrane to trap the product. This means the protein is able to contact and degrade antibiotics in the gut. “We used a microorganism that doesn’t have a periplasmic space, so the enzyme is secreted directly to the extracellular environment,” Cubillos-Ruiz says.

The researchers protected against resistance by splitting the gene for the enzyme into two inactive pieces and encoding them on separate genetic constructs. They linked each enzyme piece to protein domains that form covalent bonds with each other. After the proteins are secreted, the bond-forming domains bring the pieces of the enzyme together so the protein can reassemble in the active conformation.

“I think it’s a clever solution to an important problem,” says Nathan Crook, a metabolic engineer and synthetic biologist at North Carolina State University who studies the gut microbiome. “By splitting an antibiotic resistance gene into two parts, so that they only form an intact enzyme outside of the cell, the authors cleverly kill multiple birds with one stone. They reduce the concentration of antibiotics in the gut, and they do so using an engineered bacterium that itself is not resistant to the antibiotic nor is likely to transfer both gene fragments to another microbe.”

In mice injected with the antibiotic ampicillin, ingestion of the engineered microbes protected the mice’s gut microbiome. In addition, the mice were protected from colonization by Clostridioides difficile, a pathogenic infection that can happen when the normal microbiome is disrupted. The researchers plan to test the live therapeutic in humans. Collins says.



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