The study demonstrates that COMT inhibitors exhibit iron-dependent antibiotic activity that reshapes gut microbiota and, in an individual-specific manner, alters microbiome-mediated L‑DOPA metabolism ex vivo, revealing a drug–microbiome–drug interaction.

By uncovering a mechanistic, potentially actionable route (iron-modulated antimicrobial effects of COMT‑Is) that impacts L‑DOPA metabolism, the work suggests opportunities to predict or mitigate variable patient responses to co‑prescribed Parkinson’s medications via microbiome profiling or targeted…

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.