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Genetic engineering tool promises to aid discovery of new drugs inside microbes

Oct. 14 (UPI) — Scientists have found a new way to coax microbes into producing valuable secondary metabolites, chemical compounds that help microbes adapt to changing conditions.

Despite the contributions secondary metabolites have made to medical and material science, researchers suspect they have only barely skimmed the surface of the biochemical secrets hiding within microbes — a tool called chassis-independent recombinase-assisted genome engineering, or CRAGE, may help them unlock those secrets.

Secondary metabolites are named so because they’re non-essential. Stop a microbe from producing its primary metabolites and it is likely to die. Lock the production of secondary metabolites, however, and the microbe is sure to persist, even if at a disadvantage.

But while secondary metabolites may not be necessary for basic survival, they are necessary to thrive, and they have been an important source of agricultural, industrial and medical products.

Groups of genes called biosynthetic gene clusters are responsible for instructing the production of secondary metabolites. Different codes for different traits are constantly traded back and forth between relative microbes through a process known as horizontal gene transfer.

It’s quite difficult to study biosynthetic gene clusters and secondary metabolites. Microbes produce these compounds in response to their dynamic environs. As their conditions shift, the diversity of secondary metabolites produced by complex cellular processes also changes.

Unfortunately, when microbes are brought into the clean, sterile environs of the lab, secondary metabolite production slows to a halt.

“These metabolites are like a language that microbes use to interact with their biomes, and when isolated, they go silent,” Yasuo Yoshikuni, researcher at the Department of Energy Joint Genome Institute, said in a news release. “We currently lack the technology to stimulate microbes into activating their BGCs and synthesizing the complete product — a cellular process that involves many steps.”

Yoshikuni and his colleagues at the Energy Department’s Lawrence Berkeley National Laboratory created the CRAGE technique, which allows scientists to replicate horizontal gene transfer at high speeds.

The technology works by transplanting BGCs from one organism to a variety of potential production hosts. This technique allows researchers to more efficiently identify microbial strains that can produce secondary metabolites under laboratory conditions.

Scientists described the new technology and its many advantages this week in the journal Nature Microbiology.

“CRAGE therefore allows us to access these compounds much more readily than before,” said Helge Bode, a microbiologist at Goethe University Frankfurt in Germany. “In several cases, it has already enabled us to produce and characterize for the first time a compound of interest.”

The new technology will also help researchers begin to decipher the complex cellular machinery and production processes responsible for secondary metabolize synthesis.

“This is a landmark development, because with CRAGE we can examine how different organisms can express one gene network differently, and thus how horizontally transferred capabilities can evolve,” said David Hoyt, a chemist at the DOE Environmental Molecular Sciences Laboratory. “The previous tools to do this are much more limited.”

So far, scientists have used CRAGE to transfer target BGCs into 30 different bacterial strains. Researchers expect to broaden the scope of their efforts during followup tests. Beyond simply identifying secondary microbial production within bacteria strains, scientists suggest CRAGE can be used to actually engineer microbes to produce new proteins, RNAs and other types of molecules with a range of potential applications.

Researchers expect it won’t be long before CRAGE is being used to advance biomanufacturing and create new medical products.

“Aside from a few very well-studied microbes, the so-called model organisms like E. coli, we don’t know whether a strain will have the skills needed to perform all the steps of BGC activation,” said Yoshikuni. “Hopefully with CRAGE, we can start to shift that paradigm — we can look into more wild species and find their properties that are more suitable for a production of products and medicines.”

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