Simultaneous prescription of multiple drugs is widespread in medicine. Although the gut microbiome is implicated in drug responses, its role in mediating drug–drug interactions is unexplored. Catechol-O-methyltransferase inhibitors (COMT-I), a class of drugs used alongside levodopa (L-DOPA) to treat Parkinson’s disease symptoms, can alter microbiome composition in patients. Here we characterize the antibiotic properties of COMT-I drugs in vitro, ex vivo and in vivo and dissect how these interactions alter microbiome-mediated L-DOPA metabolism in vitro and ex vivo. Notably, in vitro iron availability determines COMT-I antibiotic activity at multiple levels: extracellular iron can drive non-enzymatic inactivation of COMT-I, rescuing COMT-I-mediated bacterial iron starvation responses. However, limitation of intracellular iron can protect sensitive bacteria from COMT-I antibiotic activity. Co-administration of COMT-I and L-DOPA to human faecal microbial communities ex vivo results in COMT-I-dependent alterations to L-DOPA metabolism in an individual-specific manner. These studies highlight a role for the gut microbiome in mediating drug–drug interactions and identify microbial features that could predict individual responses to co-prescribed drugs.

By Andrew A. Verdegaal, Joonseok Oh, Bahar Javdan, Ruojun Wang, Qihao Wu, Timothy R. W. Wang, Jaime A. González-Hernández, Mohamed S. Donia, Jason M. Crawford & Andrew L. Goodman