The Antidepressant Drug Clomipramine Inhibits the ABC Transporter BmrA

Drug uptake is constrained by epithelial barriers, such as the intestine and the blood-brain barrier, which express efflux pumps such as the ABC-transporter ABCB1. Therefore, drugs targeting the central nervous system frequently require co-administration of efflux inhibitors to facilitate sufficient target engagement. Conversely, certain drugs designed to target distinct molecular pathways may inadvertently affect ABC transporters. However, detailed functional studies of putative human ABCB1 inhibitors is challenging due to difficulties in obtaining sufficiently high amounts of protein needed. Bacterial ABC transporters, such as BmrA from Bacillus subtilis, share structural and functional similarities with ABCB1 and thus provide a reasonable alternative model system. This study investigates clomipramine, an antidepressant known to reduce multidrug resistance in human cells by a yet undefined mechanism. We demonstrate that clomipramine inhibits the ATPase activity of both full-length BmrA and its isolated nucleotide-binding domain. Using binding assays and molecular modeling, multiple clomipramine binding sites were identified in BmrA, which are also conserved in human ABCB1. Critically, one predicted site overlaps with the ATP-binding pocket. The results underscore the potential side-effects of clomipramine and highlight the value of bacterial models such as BmrA for studying novel inhibitors when studies on human proteins are not feasible.