Conjugating berberine to a multidrug resistance pump inhibitor creates an effective antimicrobial
Conjugating berberine to a multidrug resistance pump inhibitor creates an effective antimicrobial
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DOI：
10.1021/cb600238x
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Lewis, Kim
中科院分区：
文献类型：
--
作者：
Ball, Anthony R.;Casadei, Gabriele;Lewis, Kim
在细菌中，多药耐药泵(MDR)对化学上无关的两亲性毒素具有耐药性。开发有效抗生素的一个主要挑战是识别不能迅速从细菌细胞中排出的抗菌化合物。植物抗菌剂黄连素是药用植物紫锥菊和金海豹的活性成分，是一种阳离子，很容易被细菌MDR挤出，从而使其作为治疗剂相对无效。然而，抑制多药耐药外排会显著增加黄连素的抗菌活性，这表明如果能够找到有效的多药耐药泵抑制剂，小檗碱和许多其他化合物可能会更有效。在这里，我们证明了将黄连素与主要促进剂MDR的抑制剂INF55共价连接，产生了一种容易在细菌中积累的高效抗菌剂。该杂化分子在秀丽隐杆线虫肠球菌感染模型中表现出良好的疗效，治疗了病原体的蠕虫。
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 INF55, 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.