Repurposing ethyl bromopyruvate as a broad-spectrum antibacterial.
Repurposing ethyl bromopyruvate as a broad-spectrum antibacterial.
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将溴丙酮酸乙酯重新用作广谱抗菌剂。
DOI：
10.1093/jac/dky555
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Raje,ChaayaIyengar
中科院分区：
文献类型：
--
作者：
Kumar,Ajay;Boradia,VishantMahendra;Thakare,Ritesh;Singh,AlokKumar;Gani,Zahid;Das,Swetarka;Patidar,Anil;Dasgupta,Arunava;Chopra,Sidharth;Raje,Manoj;Raje,ChaayaIyengar
耐药细菌的出现是有效治疗结核分枝杆菌和ESKAPE病原体引起的感染的主要障碍。与传统的药物发现相比，药物再利用提供了一种有效而快速的方法来识别新型抗生素。方法测定溴丙酮酸乙酯的抑菌能力。结核和ESKAPE病原菌的生长抑制试验。测定了溴丙酮酸乙酯的选择性指数，并测定了对m的时效动力学。tuberculosisandStaphylococcus球菌。我们首先测试了它与批准的药物协同作用的能力，然后测试了它摧毁细菌生物膜的能力。m细胞内杀伤。在嗜中性粒细胞减少小鼠模型中测定结核和体内电位。aureusinfection。结果溴丙酮酸乙酯是一种广谱等效抗菌药物，可靶向耐药和敏感的结核分枝杆菌。结核病和ESKAPE病原体。溴丙酮酸乙酯具有浓度依赖性的杀菌活性。立即通知。溴丙酮酸乙酯抑制GAPDH，同时降低ATP水平和转铁蛋白介导的铁摄取。除GAPDH外，该化合物对丙酮酸激酶、异柠檬酸裂解酶和苹果酸合成酶均有不同程度的抑制作用。溴丙酮酸乙酯与任何药物均无负相互作用，并以比万古霉素低64倍的浓度显著减少生物膜。在金黄色葡萄球菌中性粒细胞减少的大腿感染模型中，溴丙酮酸乙酯的效果与万古霉素相当，且剂量为其1/25。结论溴丙酮酸乙酯具有广谱抗菌药物的特点。
BackgroundThe emergence of drug-resistant bacteria is a major hurdle for effective treatment of infections caused byMycobacterium tuberculosisand ESKAPE pathogens. In comparison with conventional drug discovery, drug repurposing offers an effective yet rapid approach to identifying novel antibiotics.MethodsEthyl bromopyruvate was evaluated for its ability to inhibitM. tuberculosisand ESKAPE pathogens using growth inhibition assays. The selectivity index of ethyl bromopyruvate was determined, followed by time–kill kinetics againstM. tuberculosisandStaphylococcus aureus. We first tested its ability to synergize with approved drugs and then tested its ability to decimate bacterial biofilm. Intracellular killing ofM. tuberculosiswas determined andin vivopotential was determined in a neutropenic murine model ofS. aureusinfection.ResultsWe identified ethyl bromopyruvate as an equipotent broad-spectrum antibacterial agent targeting drug-susceptible and -resistantM. tuberculosisand ESKAPE pathogens. Ethyl bromopyruvate exhibited concentration-dependent bactericidal activity. InM. tuberculosis, ethyl bromopyruvate inhibited GAPDH with a concomitant reduction in ATP levels and transferrin-mediated iron uptake. Apart from GAPDH, this compound inhibited pyruvate kinase, isocitrate lyase and malate synthase to varying extents. Ethyl bromopyruvate did not negatively interact with any drug and significantly reduced biofilm at a 64-fold lower concentration than vancomycin. When tested in anS. aureusneutropenic thigh infection model, ethyl bromopyruvate exhibited efficacy equal to that of vancomycin in reducing bacterial counts in thigh, and at 1/25th of the dosage.ConclusionsEthyl bromopyruvate exhibits all the characteristics required to be positioned as a potential broad-spectrum antibacterial agent.
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影响因子：
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作者：
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DOI：
--
发表时间：
1982
期刊：
Clinical Immunology and Immunopathology
影响因子：
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作者：
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DOI：
--
发表时间：
1984
期刊：
影响因子：
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作者：
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DOI：
10.1089/aid.1.1983.1.407
发表时间：
1984
期刊：
AIDS research
影响因子：
--
作者：
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通讯作者：
Volsky,DJ