Dwivedi Gaurav Raj, Tiwari Nimisha, Singh Aastha, Kumar Akhil, Roy Sudeep, Negi Arvind Singh, Pal Anirban, Chanda Debabrata, Sharma Ashok, Darokar Mahendra P
Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Near Kukrail Picnic Spot, P.O. CIMAP, Lucknow, 226015, India.
School of Environmental Science, Babasaheb Bhim Rao Ambedkar University, Lucknow, 226025, UP, India.
Appl Microbiol Biotechnol. 2016 Mar;100(5):2311-25. doi: 10.1007/s00253-015-7152-6. Epub 2015 Dec 12.
The purpose of the present study was to study the synergy potential of gallic acid-based derivatives in combination with conventional antibiotics using multidrug resistant cultures of Escherichia coli. Gallic acid-based derivatives significantly reduced the MIC of tetracycline against multidrug resistant clinical isolate of E. coli. The best representative, 3-(3',4,'5'-trimethoxyphenyl)-4,5,6-trimethoxyindanone-1, an indanone derivative of gallic acid, was observed to inhibit ethidium bromide efflux and ATPase which was also supported by in silico docking. This derivative extended the post-antibiotic effect and decreased the mutation prevention concentration of tetracycline. This derivative in combination with TET was able to reduce the concentration of TNFα up to 18-fold in Swiss albino mice. This derivative was nontoxic and well tolerated up to 300 mg/kg dose in subacute oral toxicity study in mice. This is the first report of gallic acid-based indanone derivative as drug resistance reversal agent acting through ATP-dependent efflux pump inhibition.
本研究的目的是利用大肠杆菌的多重耐药培养物，研究基于没食子酸的衍生物与传统抗生素联合使用时的协同潜力。基于没食子酸的衍生物显著降低了四环素对多重耐药临床分离大肠杆菌的最低抑菌浓度（MIC）。观察到最佳代表物，没食子酸的茚满酮衍生物3-(3',4,'5'-三甲氧基苯基)-4,5,6-三甲氧基茚满酮-1，可抑制溴化乙锭外排和ATP酶，计算机模拟对接也支持这一点。该衍生物延长了抗生素后效应，并降低了四环素的防突变浓度。该衍生物与四环素（TET）联合使用能够使瑞士白化小鼠体内的肿瘤坏死因子α（TNFα）浓度降低多达18倍。在小鼠亚急性口服毒性研究中，该衍生物无毒，在高达300mg/kg剂量时耐受性良好。这是关于基于没食子酸的茚满酮衍生物作为通过抑制ATP依赖性外排泵发挥作用的耐药逆转剂的首次报道。
