Scientists Hijack Bacteria to Make Drugs Easy to Make
AUSTIN, Texas – For more affordable and sustainable drug options than we have today, the drugs we use to treat high blood pressure, pain or memory loss may someday come from engineered bacteria, cultured in vats like yogurt. And thanks to a new bacterial tool developed by scientists at The University of Texas at Austin, the process of increasing drug-making in bacterial cells may be happening more quickly than we think.
For decades, researchers have been looking for ways to make drug manufacturing more affordable and sustainable than current pharmaceutical manufacturing processes, many of which rely on plants or petroleum. Using bacteria has been suggested as a good organic alternative, but detecting and optimizing the production of therapeutic molecules is difficult and time-consuming, taking months. In a new paper this week in Nature Chemical Biology, the UT Austin team introduces a biosensor system, derived from the bacterium E. coli, that can be adapted to detect all types of therapeutic compounds accurately and in just a few hours.
“We’re looking at ways to provide bacteria with ‘sense’, similar to olfactory receptors or taste receptors, and use them to detect the various compounds they might make,” said Andrew Ellington, professor of molecular biosciences and correspondent author on the paper.
Many of the medicines we use are made with ingredients extracted from plants (for example, morphine, a narcotic painkiller derived from poppies, or galantamine, a medicine for dementia treatment derived from lilies). Extracting medicine from this plant is complex and resource-intensive, requiring both water and acreage to grow the plant. Supply chains are easily disrupted. And crops can be damaged by floods, fires, and droughts. Obtaining similar therapeutic components using synthetic chemistry also poses problems, as the process relies on petroleum and petroleum-based products associated with waste and costs.
Enter simple bacteria, a cheap, efficient and sustainable alternative. The genetic code of bacteria can be easily manipulated to become a drug manufacturing plant. In a process called biosynthesis, the biological systems of bacteria are harnessed to produce specific molecules as part of natural cellular processes. And bacteria can replicate at high speed. All they need to do the job is sugar.
Unfortunately, manufacturers have not had a way to rapidly analyze different types of engineered bacteria to identify bacteria capable of producing the desired amount of drug at commercial volumes – until now. Accurately analyzing thousands of engineered strains en route to a good manufacturer can take weeks or months with current technology, but only a day with a new biosensor.
“There are currently no biosensors for most plant metabolites,” said Simon d’Oelsnitz, a research scientist in the Department of Molecular Biosciences and first author of the paper. “With this technique, it should be possible to create biosensors for a wide variety of drugs.”
The biosensor developed by d’Oelsnitz, Ellington and colleagues quickly and accurately determines the number of specific molecules produced by bacterial strains. The team developed biosensors for several common medications, such as cough suppressants and vasodilators, which are used to treat muscle spasms. Molecular images of the biosensor taken by X-ray crystallographers Wantae Kim and Yan Jessie Zhang show exactly how they gripped their partner’s drug tightly. When the drug is detected by the biosensor, it glows. Additionally, the team engineered their own bacteria to produce compounds found in several FDA-approved drugs and used biosensors to analyze product output, essentially demonstrating how industry can adopt biosensors to optimize chemical manufacturing quickly.
“While this is not the first biosensor,” says d’Oelsnitz, “the technique allows them to be developed faster and more efficiently. In turn, that opens the door for more drugs to be produced using biosynthesis.”
Wantae Kim, Nathaniel T. Burkholder, Kamyab Javanmardi, Yan Jessie Zhang and Hal Alper from UT Austin and Ross Thyer, formerly from UT Austin and now at Rice University, collaborated on this research. The research was funded by the Defense Advanced Research Projects Agency, The Welch Foundation, the Air Force Office of Scientific Research and the National Institutes of Health. Ellington holds Regent Chair Nancy Lee and Perry R. Bass in Molecular Biology.
The University of Texas at Austin is committed to transparency and disclosure of all potential conflicts of interest. University researchers involved in this study have submitted the required financial disclosure forms to the university. UT Austin and its researchers filed a patent application for the technology described here.
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