A scalable metabolite supplementation strategy against antibiotic resistant pathogen Chromobacterium violaceum induced by NAD(+)/NADH(+) imbalance.
A scalable metabolite supplementation strategy against antibiotic resistant pathogen Chromobacterium violaceum induced by NAD(+)/NADH(+) imbalance.
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DOI：
10.1186/s12918-017-0427-z
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发表时间：
2017-04-26
影响因子：
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通讯作者：
Raghunathan A
中科院分区：
文献类型：
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作者：
Banerjee D;Parmar D;Bhattacharya N;Ghanate AD;Panchagnula V;Raghunathan A
全球抗生素耐药性问题的前沿需要新的治疗策略。本研究开发了一种新的系统生物学驱动的方法，用于使用良性代谢物杀死抗生素耐药病原体。控制实验室进化建立了对氯霉素和链霉素耐药的色杆菌病原体。这些耐药病原体显示出更高的生长速度，需要更高的致死剂量的抗生素。生长和活力测试确定苹果酸盐、马来酸盐、琥珀酸盐、丙酮酸盐和氧己二酸盐作为抗生素治疗的再敏剂。抗性基因通过全基因组测序进行编目。细胞内代谢组学分析鉴定出紫罗兰素是耐药的潜在生物标志物。代谢物的时间变化捕获了稳定状态周围的线性化动态，并与生长速率相关。采用基于约束的核心代谢通量平衡模型预测抗生素敏感性和耐药性的代谢基础。该模型预测了氯霉素和链霉素等抗生素导致的电子失衡和NAD/NADH比例偏斜。抗性病原体重新连接其代谢网络以补偿氧化还原稳态的破坏。我们预见这种可扩展的工作流程在确定临床分离物代谢物方面的效用，作为减轻抗生素耐药性的必然解决方案。本文的在线版本（doi:10.1186/s12918-017-0427-z）包含补充材料，可供授权用户使用。
The leading edge of the global problem of antibiotic resistance necessitates novel therapeutic strategies. This study develops a novel systems biology driven approach for killing antibiotic resistant pathogens using benign metabolites. Controlled laboratory evolutions established chloramphenicol and streptomycin resistant pathogens of Chromobacterium. These resistant pathogens showed higher growth rates and required higher lethal doses of antibiotic. Growth and viability testing identified malate, maleate, succinate, pyruvate and oxoadipate as resensitising agents for antibiotic therapy. Resistant genes were catalogued through whole genome sequencing. Intracellular metabolomic profiling identified violacein as a potential biomarker for resistance. The temporal variance of metabolites captured the linearized dynamics around the steady state and correlated to growth rate. A constraints-based flux balance model of the core metabolism was used to predict the metabolic basis of antibiotic susceptibility and resistance. The model predicts electron imbalance and skewed NAD/NADH ratios as a result of antibiotics – chloramphenicol and streptomycin. The resistant pathogen rewired its metabolic networks to compensate for disruption of redox homeostasis. We foresee the utility of such scalable workflows in identifying metabolites for clinical isolates as inevitable solutions to mitigate antibiotic resistance. The online version of this article (doi:10.1186/s12918-017-0427-z) contains supplementary material, which is available to authorized users.