Enhancement of Antibiotic Activity against Multidrug-Resistant Bacteria by the Efflux Pump Inhibitor 3,4-Dibromopyrrole-2,5-dione Isolated from a Pseudoalteromonas sp.
Enhancement of Antibiotic Activity against Multidrug-Resistant Bacteria by the Efflux Pump Inhibitor 3,4-Dibromopyrrole-2,5-dione Isolated from a Pseudoalteromonas sp.
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DOI：
10.1021/np500775e
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发表时间：
2015-03-01
影响因子：
5.1
通讯作者：
Mincer, Tracy J.
中科院分区：
文献类型：
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作者：
Whalen, Kristen E.;Poulson-Ellestad, Kelsey L.;Mincer, Tracy J.
外排泵的耐药细胞分裂（RND）成员在革兰氏阴性菌的多药耐药（MDR）中起重要作用。在这里，我们描述了从海洋微生物提取物中寻找新的小分子来阻止外排，从而恢复MDR细菌菌株的抗生素敏感性。我们报道了从肠杆菌科和铜绿假单胞菌中分离出的RND转运体抑制剂3，4-二溴吡咯-2，5-二酮（1）。在过表达三种原型RND转运蛋白（AcrAB-TolC、MexAB-OprM和MexXY-OprM）的菌株中，3，4-二溴吡咯-2，5-二酮使两种氟喹诺酮类、氨基糖苷类、大环内酯类、β-内酰胺类、四环素和氯霉素的最低抑菌浓度（MIC）降低2- 16倍。3，4-二溴吡咯-2，5-二酮还增加了Hoechst 33342在野生型菌株中的细胞内蓄积，但在转运蛋白缺陷型菌株中不增加，并阻止了H33342外排（IC 50 = 0.79 μ g/mL或3 μ M），这是外排泵抑制剂（EPI）功能的标志。对36株假交替单胞菌分离株的代谢组学调查显示，主要溴化代谢物仅存在于杀鱼假单胞菌系统发育进化枝内，其中还观察到大多数抗生素活性，这表明卤化和增强的次级代谢物生物合成潜力之间存在联系。总之，3，4-二溴吡咯-2，5-二酮是一种有效的EPI，值得进一步关注，作为一种佐剂，以提高现有抗生素的有效性。
Members of the resistance nodulation cell division (RND) of efflux pumps play essential roles in multidrug resistance (MDR) in Gram-negative bacteria. Here, we describe the search for new small molecules from marine microbial extracts to block efflux and thus restore antibiotic susceptibility in MDR bacterial strains. We report the isolation of 3,4-dibromopyrrole-2,5-dione (1), an inhibitor of RND transporters, from Enterobacteriaceae and Pseudomonas aeruginosa, from the marine bacterium Pseudoalteromonas piscicida. 3,4-Dibromopyrrole-2,5-dione decreased the minimum inhibitory concentrations (MICs) of two fluoroquinolones, an aminoglycoside, a macrolide, a beta-lactam, tetracycline, and chloramphenicol between 2- and 16-fold in strains overexpressing three archetype RND transporters (AcrAB-TolC, MexAB-OprM, and MexXY-OprM). 3,4-Dibromopyrrole-2,5-dione also increased the intracellular accumulation of Hoechst 33342 in wild-type but not in transporter-deficient strains and prevented H33342 efflux (IC50 = 0.79 mu g/mL or 3 mu M), a hallmark of efflux pump inhibitor (EPI) functionality. A metabolomic survey of 36 Pseudoalteromonas isolates mapped the presence of primarily brominated metabolites only within the P. piscicida phylogenetic clade, where a majority of antibiotic activity was also observed, suggesting a link between halogenation and enhanced secondary metabolite biosynthetic potential. In sum, 3,4-dibromopyrrole-2,5-dione is a potent EPI and deserves further attention as an adjuvant to enhance the effectiveness of existing antibiotics.