13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine
13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine
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DOI：
10.3390/antibiotics8040212
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发表时间：
2019-12-01
影响因子：
4.8
通讯作者：
Kawamura, Yoshiaki
中科院分区：
文献类型：
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作者：
Kotani, Kenta;Matsumura, Mio;Kawamura, Yoshiaki
我们之前的研究表明，小檗碱可以减弱铜绿假单胞菌对MexXY外排依赖的氨基糖苷类药物的耐药性。在这里，我们的目标是合成具有较高的MexXY抑制活性的小檗碱衍生物。我们合成了11种小檗碱衍生物，其中13-（2-甲基苄基）小檗碱（13-o- mbb）表现出最有希望的MexXY抑制活性，而其构构体则没有。13-o-MBB对高度耐多药铜绿假单胞菌的各种氨基糖苷的最低抑制浓度（mic）降低了4-至128倍。此外，13-o-MBB显著降低了庆大霉素和氨基卡星在木糖氧化无色杆菌和洋葱伯克氏菌中的mic。分数抑制浓度指数表明，13-o-MBB仅在mexxy阳性铜绿假单胞菌中与氨基糖苷协同作用。时间杀伤曲线显示，13-o-MBB或更高浓度的小檗碱通过抑制铜绿假单胞菌中的MexXY而提高庆大霉素的杀菌活性。我们的研究结果表明，13-o-MBB比小檗碱更能抑制MexXY依赖的氨基糖苷耐药，13-o-MBB是一种有效的MexXY氨基糖苷耐药抑制剂。
We previously showed that berberine attenuates MexXY efflux-dependent aminoglycoside resistance in Pseudomonas aeruginosa. Here, we aimed to synthesize berberine derivatives with higher MexXY inhibitory activities. We synthesized 11 berberine derivatives, of which 13-(2-methylbenzyl) berberine (13-o-MBB) but not its regiomers showed the most promising MexXY inhibitory activity. 13-o-MBB reduced the minimum inhibitory concentrations (MICs) of various aminoglycosides 4- to 128 fold for a highly multidrug resistant P. aeruginosa strain. Moreover, 13-o-MBB significantly reduced the MICs of gentamicin and amikacin in Achromobacter xylosoxidans and Burkholderia cepacia. The fractional inhibitory concentration indices indicated that 13-o-MBB acted synergistically with aminoglycosides in only MexXY-positive P. aeruginosa strains. Time-kill curves showed that 13-o-MBB or higher concentrations of berberine increased the bactericidal activity of gentamicin by inhibiting MexXY in P. aeruginosa. Our findings indicate that 13-o-MBB inhibits MexXY-dependent aminoglycoside drug resistance more strongly than berberine and that 13-o-MBB is a useful inhibitor of aminoglycoside drug resistance due to MexXY.