4-Hydroxy- a- Tetralone and its Derivative as Drug Resistance Reversal Agents in Multi Drug Resistant Escherichia coli
4-Hydroxy- a- Tetralone and its Derivative as Drug Resistance Reversal Agents in Multi Drug Resistant Escherichia coli
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DOI：
10.1111/cbdd.12263
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发表时间：
2014-04-01
影响因子：
3
通讯作者：
Darokar, Mahendra P.
中科院分区：
文献类型：
--
作者：
Dwivedi, Gaurav R.;Upadhyay, Harish C.;Darokar, Mahendra P.
本研究的目的是利用多重耐药大肠杆菌（MDREC）了解从羊草属（Ammannia spp.）分离的4-羟基四酮(1)及其半合成衍生物（1a-1e）的耐药逆转机制。试验化合物本身没有明显的抗菌活性，但它们联合使用可以降低四环素（TET）的最低抑制浓度（MIC）。在时间杀伤实验中，化合物1及其衍生物1e与TET联合作用使细胞活力呈浓度依赖性降低。化合物1和1e也能降低TET的防突变浓度。两种化合物均表现出ATP依赖性外排泵的抑制作用。在实时聚合酶链反应（RT-PCR）研究中，化合物1和1e单独及联合TET均显著下调编码多药ATP结合盒（ABC）转运蛋白的外排泵基因（yojI）的表达。分子机制也得到了硅对接研究的支持，发现化合物1和1e与YojI具有显著的结合亲和力。本研究证实，化合物1及其衍生物1e是ABC外排泵抑制剂，这可能是开发用于管理耐多药感染的廉价天然产物的抗菌组合的基础。
The purpose of present investigation was to understand the drug resistance reversal mechanism of 4-hydroxy--tetralone (1) isolated from Ammannia spp. along with its semi-synthetic derivatives (1a-1e) using multidrug resistant Escherichia coli (MDREC). The test compounds did not show significant antibacterial activity of their own, but in combination, they reduced the minimum inhibitory concentration (MIC) of tetracycline (TET). In time kill assay, compound 1 and its derivative 1e in combination with TET reduced the cell viability in concentration dependent manner. Compounds 1 and 1e were also able to reduce the mutation prevention concentration of TET. Both compounds showed inhibition of ATP dependent efflux pumps. In real time polymerase chain reaction (RT-PCR) study, compounds 1 and 1e alone and in combination with TET showed significant down expression of efflux pump gene (yojI) encoding multidrug ATP binding cassettes (ABC) transporter protein. Molecular mechanism was also supported by the in silico docking studies, which revealed significant binding affinity of compounds 1 and 1e with YojI. This study confirms that compound 1 and its derivative 1e are ABC efflux pump inhibitors which may be the basis for development of antibacterial combinations for the management of MDR infections from inexpensive natural product.