In a recent study, researchers at the University of California, San Francisco described the first concrete example of how a microbiome can interfere with the intended effects of a drug. They focus on L-dopa, the main treatment for Parkinson's disease, which identifies which of the trillions of bacteria are responsible for degrading drugs and how to prevent this microbial interference.
Parkinson's disease attacks nerve cells that produce dopamine in the brain. Without such nerve cells, the body experiences tremors, muscle stiffness, and balance and coordination problems. Levodopa delivers dopamine to the brain to relieve symptoms, however, only about 1% to 5% of the drugs actually reach the brain.
This number and the efficacy of the drug vary from patient to patient. Since the introduction of levodopa in the late 1960s, researchers have known that the body's enzymes (the tools that carry out the necessary chemistry) can break down levodopa in the intestines and prevent drugs from entering the brain. Therefore, the pharmaceutical industry has introduced a new drug, carbidopa, to prevent unnecessary levodopa metabolism.
“Despite this, there is a lot of metabolisms that are unexplained and varies greatly from person to person.” Maini Rekdal said. Not only does the drug work poorly for some patients, but when L-dopa is converted to extracerebral In the case of dopamine, the compound can cause side effects including severe gastrointestinal distress and arrhythmias. If fewer drugs reach the brain, patients often control their symptoms by overdosing, which can exacerbate side effects.
Maini Rekdal suspects that microbes may be the cause of the disappearance of L-dopa. Because previous studies have shown that antibiotics can improve patients' response to levodopa, scientists speculate that bacteria may be the culprit. Still, no one has determined which bacteria are the “culprits”.
Using the Human Microbiome project as a reference, Maini Rekdal and his team used bacterial DNA to find out which gut microbes have genes encoding similar enzymes. There are several microorganisms that meet their standards, and only one of them is Enterococcus faecalis (E. faecalis), which is able to metabolize all levodopa.
Based on this discovery, the team provided the first strong evidence linking E. faecalis and bacterial enzymes (PLP-dependent tyrosine decarboxylase or TyrDC) to L-dopa metabolism. Even though humans and bacterial enzymes perform exactly the same chemical reaction, the bacteria look a little different. Maini Rekdal speculates that carbidopa may not penetrate microbial cells, or that slight structural differences may prevent the drug from interacting with bacterial enzymes.
Balskus and her team have discovered a molecule that inhibits bacterial enzymes. "The molecule shuts down this unnecessary bacterial metabolism without killing the bacteria," says Maini Rekdal. This species, along with compounds similar to it, can provide a starting point for the development of new drugs to improve the efficacy of levodopa in patients with Parkinson's disease.
Reference:
- Maini Rekdal el al., Science (2019). science.sciencemag.org/cgi/doi … 1126/science.aau6323