Repurposing bioactive aporphine alkaloids as efflux pump inhibitors

• Published in: Fitoterapia Vol. 139; p. 104371
• Main Authors: Avci, Fatma Gizem, Atas, Basak, Aksoy, Cemile Selin, Kurpejovic, Eldin, Gulsoy Toplan, Gizem, Gurer, Caglayan, Guillerminet, Maxime, Orelle, Cedric, Jault, Jean-Michel, Sariyar Akbulut, Berna
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-11-2019; Elsevier Science Ltd; Elsevier
• Subjects: Alkaloid; Alkaloids; Alkaloids - pharmacology; Anti-Bacterial Agents - pharmacology; Aporphines - pharmacology; Bacillus subtilis - drug effects; Bacterial Proteins - antagonists & inhibitors; Berberine; Berberine - pharmacology; Biological activity; Biological Transport; Bmr; BmrA; Combinatorial analysis; Conjugation; Doxorubicin; Drug Repositioning; Drug Synergism; Drugs; E coli; Efflux; Efflux pump inhibition; Escherichia coli - drug effects; Extrusion; Growth rate; Inhibitors; Life Sciences; Membrane Transport Proteins; Membrane vesicles; Microbial Sensitivity Tests; Molecular Structure; Natural products; Papaver - chemistry; Plant Components, Aerial - chemistry; Pumps; Ribonucleic acid; RNA; Roemerine; Scanning electron microscopy; Substrates; Transport; Turkey; Turkey; Berberine; Alkaloid; BmrA; Efflux pump inhibition; Roemerine; Bmr
• ISSN: 0367-326X; 1873-6971
• DOI: 10.1016/j.fitote.2019.104371

Extrusion of drugs or drug-like compounds through bacterial efflux pumps is a serious health issue that leads to loss in drug efficacy. Combinatorial therapies of low-efficacy drugs with efflux pump inhibitors may help to restore the activities of such drugs. In this quest, natural products are attractive molecules, since in addition to their wide range of bioactivities they may inhibit efflux pumps. The current work repurposed the bioactive alkaloid roemerine as a potential efflux pump inhibitor. In Bacillus subtilis, both Bmr and BmrA, belonging to the major facilitator and the ATP-binding cassette superfamilies, respectively, were found to be inhibited by roemerine. Scanning electron microscopy and RNA-Seq analyses showed that it potentiated the effect of berberine. Growth rates and checkerboard assays confirmed the synergy of roemerine and berberine and that roemerine prevented berberine efflux by inhibiting Bmr. Transport assays with inverted membrane vesicles prepared from Escherichia coli overexpressing BmrA showed that increasing roemerine concentration decreased the transport of doxorubicin, the BmrA substrate, confirming that roemerine may also be considered as an inhibitor of BmrA. Thus, these findings suggest that conjugation of roemerine to substrates of efflux pumps, Bmr and BmrA, may help to potentiate the activity of their drug substrates.
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•Extrusion of drugs or drug-like compounds reduces drug efficacy.•Three bioactive alkaloids were repurposed as efflux pump inhibitors.•Roemerine inhibits the Bmr and BmrA pumps of B. subtilis.•Roemerine will potentiate the activities of drug substrates of Bmr and BmrA.