title: Conjugating berberine to a multidrug efflux pump inhibitor creates an effective antimicrobial.
abstract: In bacteria, multidrug-resistance pumps (MDRs) confer resistance to chemically unrelated amphipathic toxins. A major challenge in developing efficacious antibiotics is identifying antimicrobial compounds that are not rapidly pumped out of bacterial cells. The plant antimicrobial berberine, the active component of the medicinal plants echinacea and golden seal, is a cation that is readily extruded by bacterial MDRs, thereby rendering it relatively ineffective as a therapeutic agent. However, inhibition of MDR efflux causes a substantial increase in berberine antimicrobial activity, suggesting that berberine and potentially many other compounds could be more efficacious if an effective MDR pump inhibitor could be identified. Here we show that covalently linking berberine to INF 55 , an inhibitor of Major Facilitator MDRs, results in a highly effective antimicrobial that readily accumulates in bacteria. The hybrid molecule showed good efficacy in a Caenorhabditis elegans model of enterococcal infection, curing worms of the pathogen.
authors.affiliation: Department of Biology and Antimicrobial Discovery Center, Northeastern University, Boston, Massachusetts 02115, USA.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Ball
authors.forename: Gabriele
authors.initials: G
authors.lastname: Casadei
authors.forename: Siritron
authors.initials: S
authors.lastname: Samosorn
authors.forename: John B
authors.initials: JB
authors.lastname: Bremner
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Ausubel
authors.forename: Terence I
authors.initials: TI
authors.lastname: Moy
authors.forename: Kim
authors.initials: K
authors.lastname: Lewis
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy / Q000517:prevention & control*; D018407:Bacterial Physiological Phenomena; D001599:Berberine / Q000737:chemistry* / Q000494:pharmacology; D017173:Caenorhabditis elegans; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D020900:Echinacea / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D010936:Plant Extracts / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D010936:Plant Extracts; D001599:Berberine