2019 International Grant winner

The projects related to the following areas of research will be considered for funding:

• Gut microbiota metabolism/ chemical transformation of drugs with impact on drug efficacy or their adverse events profile
• Gut microbiota influence of drug pharmacokinetics (independently of direct transformation) with impact on drug efficacy or their adverse event profile

-

The human gut is home to trillions of bacteria and other microbes that play important roles in human health and disease. This microbial community (the human gut microbiota) also interacts with small molecule drugs, altering their chemical structures and thereby changing the activity and toxicity of these medications.

We have recently discovered the details of how the gut microbiota metabolizes Levodopa (L-dopa), an important Parkinson’s disease medication. L-dopa must enter the brain to be effective, and transformation of this drug in the gut by microbes can negatively affect drug availability.

This project will explore a strategy for preventing this unwanted activity: a small molecule drug that inhibits gut microbial metabolism of L-dopa.

In our preliminary work, we found that while drugs targeting host peripheral metabolism are ineffective toward the key bacterial enzyme involved in L-dopa metabolism, we were able to identify an inhibitor that can stop gut microbial L-dopa metabolism in whole cells and complex patient microbiotas. We will optimize our initial lead compound using chemical synthesis and test its activity in animals, including a model of Parkinson’s disease.

Altogether, this work will demonstrate that it is possible to control unwanted gut microbial drug metabolism in a complex environment, providing a critical support for this new concept in therapeutics and personalized medicine.