Lethal synergy involving bicyclomycin: an approach for reviving old antibiotics
Lethal synergy involving bicyclomycin: an approach for reviving old antibiotics
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DOI：
10.1093/jac/dku285
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发表时间：
2014-12-01
影响因子：
5.2
通讯作者：
Drlica, Karl
中科院分区：
文献类型：
--
作者：
Malik, Muhammad;Li, Liping;Drlica, Karl
解决日益严重的抗菌素耐药性问题的一种方法是恢复可能具有被保护性因素掩盖的内在致死活性的旧化合物。双环霉素是一种古老的 Rho 转录终止子抑制剂，其本身几乎没有表现出快速致死活性。然而，双环霉素参与抑菌协同作用，这提出了可能存在致死协同作用条件的可能性，也许是通过抑制保护因子。将双环霉素与基因表达的抑菌抑制剂联合使用，并用几种培养的革兰氏阴性病原体测量了杀菌活性。单独使用时，双环霉素未能快速杀死正在生长的大肠杆菌培养物；然而，额外存在抑菌浓度的四环素、氯霉素或利福平会导致快速死亡。当双环霉素与四环素或利福平联合使用时，其他四种病原体，鲍曼不动杆菌、肺炎克雷伯菌、肠沙门氏菌血清型鼠伤寒和志贺氏菌，也表现出增强的杀灭作用。对于组合测试的所有药物来说，这种致命的协同作用是在低浓度（略高于 MIC）下实现的。对大肠杆菌的后续研究表明，致命的协同作用是由转录延伸的阻断引起的。此外，当双环霉素在四环素之前60分钟添加时，致死协同作用降低，这表明双环霉素诱导了保护因子。双环霉素的作用说明了一种基本上被废弃的抗菌剂中存在的潜力；当与已知的基因表达抑菌抑制剂共同给药时，它表现出致命的协同作用。目前尚未表征的保护因素的识别可能会揭示促进某些旧抗生素致命作用的新方法。
One way to address the growing problem of antimicrobial resistance is to revive old compounds that may have intrinsic lethal activity that is obscured by protective factors. Bicyclomycin is an old inhibitor of the Rho transcription terminator that by itself shows little rapid lethal activity. However, bicyclomycin participates in bacteriostatic synergy, which raises the possibility that conditions for lethal synergy may exist, perhaps through a suppression of protective factors.Bicyclomycin was combined with bacteriostatic inhibitors of gene expression, and bactericidal activity was measured with several cultured Gram-negative pathogens.When used alone, bicyclomycin failed to rapidly kill growing cultures of Escherichia coli; however, the additional presence of bacteriostatic concentrations of tetracycline, chloramphenicol or rifampicin led to rapid killing. Four other pathogen species, Acinetobacter baumannii, Klebsiella pneumoniae, Salmonella enterica serotype Typhimurium and Shigella dysenteriae, also exhibited enhanced killing when bicyclomycin was combined with tetracycline or rifampicin. This lethal synergy was achieved at low concentrations (slightly above the MIC) for all agents tested in combinations. Follow-up work with E. coli indicated that lethal synergy arose from a blockage of transcription elongation. Moreover, lethal synergy was reduced when bicyclomycin was added 60 min before tetracycline, suggesting that bicyclomycin induces a protective factor.The action of bicyclomycin illustrates the potential present in a largely abandoned antibacterial agent; it exhibits lethal synergy when coadministered with known, bacteriostatic inhibitors of gene expression. The identification of protective factors, which are currently uncharacterized, may reveal new ways to promote the lethal action of some old antibiotics.