Gut microbes are thought to metabolize the Parkinson’s disease drug levodopa, limiting the drug’s effectiveness and causing adverse side effects. But the exact organisms responsible for this activity are unknown.
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Researchers have found that Enterococcus faecalis absorbs levodopa and converts it to dopamine, while Eggerthella lenta converts dopamine into meta-tyramine, a compound that may contribute to some of levodopa’s side effects. What’s more, the team identified a small molecule that blocks the bacterial pathway that metabolizes levodopa.
The findings could provide a starting point for the development of new drugs to improve levodopa therapy for people with Parkinson’s disease.
Specific gut bacteria can break down levodopa, a drug that’s used to treat many of the symptoms experienced by people with Parkinson’s disease, making the medication less effective and contributing to its side effects. The study, published in Science, could provide a starting place for the development of new drugs to improve levodopa therapy.
In the brain of people with Parkinson’s disease, dopamine becomes progressively depleted, causing tremor, rigidity, and slowness of movement. Levodopa, the precursor of dopamine, works by passing the blood-brain barrier and releasing dopamine in the brain. But some of the drug is converted to dopamine before it gets to the brain, which can cause adverse side effects and limit the drug’s effectiveness.
Breaking down levodopa
Because antibiotics improve people’s response to levodopa, scientists had suspected that gut microbes could metabolize the drug. But little was known about the exact organisms responsible for this activity.
So Vayu Maini Rekdal at Harvard University and his colleagues scoured the DNA of gut bacteria for microbes that could be able to convert levodopa to dopamine.
The researchers found that Enterococcus faecalis absorbs levodopa, and it produces an enzyme that converts levodopa to dopamine.
Blocking bacterial activity
The enzyme produced by Enterococcus faecalis is not inhibited by carbidopa, a drug that blocks the conversion of levodopa into dopamine by a human enzyme.
Because the human enzyme is similar but not identical to the bacterial enzyme, the scientists say that this slight structural difference may prevent carbidopa from interacting with the bacterial enzyme. Alternatively, carbidopa may not be able to penetrate the microbial cells.
However, the team discovered a molecule, called (S)-α-fluoromethyltyrosine, that is able to inhibit the bacterial enzyme without killing the bacteria.
What’s more, the researchers found that the gut bacterium Eggerthella lenta is able to convert dopamine into meta-tyramine, a compound that may contribute to some of levodopa’s side effects.
Further research is needed to investigate whether inhibiting the levodopa-metabolizing activity of gut microbes could improve treatment efficacy and outcomes for people with Parkinson’s disease, the scientists say.