Potentiating antibacterial activity by predictably enhancing endogenous microbial ROS production.
Potentiating antibacterial activity by predictably enhancing endogenous microbial ROS production.
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DOI：
10.1038/nbt.2458
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发表时间：
2013-02
影响因子：
46.9
通讯作者：
中科院分区：
文献类型：
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抗药性感染的发病率不断增加，加上新抗生素的供应渠道薄弱，造成了全球公共卫生危机。因此，需要新的策略来增强我们的抗生素库。由于抗生素通过诱导活性氧（ROS）部分杀死细菌，因此我们推断靶向微生物ROS产生可能会增强抗生素活性。在这里，我们表明大肠杆菌中活性氧的产生可以预见地增强，从而增加细菌对氧化攻击的易感性。我们开发了一个整体的，基因组规模的代谢建模方法，能够预测活性氧在大肠杆菌的生产。杆菌系统地扰动代谢网络，并分析其通量分布，以确定预测增加ROS产生的靶点。通过实验验证了计算机预测的目标，并显示出对氧化剂的敏感性增加。经过验证的靶点也增加了对抗生素杀伤的敏感性。这项工作建立了一种基于系统的方法来调节细菌中ROS的产生，并证明增加微生物ROS的产生可以增强氧化剂和抗生素的杀伤作用。
The ever-increasing incidence of antibiotic-resistant infections combined with a weak pipeline of new antibiotics has created a global public health crisis. Accordingly, novel strategies for enhancing our antibiotic arsenal are needed. As antibiotics kill bacteria in part by inducing reactive oxygen species (ROS), we reasoned that targeting microbial ROS production might potentiate antibiotic activity. Here we show that ROS production can be predictably enhanced in Escherichia coli, increasing the bacteria’s susceptibility to oxidative attack. We developed an ensemble, genome-scale metabolic modeling approach capable of predicting ROS production in E. coli. The metabolic network was systematically perturbed and its flux distribution analyzed to identify targets predicted to increase ROS production. In silico–predicted targets were experimentally validated and shown to confer increased susceptibility to oxidants. Validated targets also increased susceptibility to killing by antibiotics. This work establishes a systems-based method to tune ROS production in bacteria and demonstrates that increased microbial ROS production can potentiate killing by oxidants and antibiotics.
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影响因子：
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作者：
Jamshidi, Neema;Palsson, Bernhard O
通讯作者：
Palsson, Bernhard O
影响因子：
64.5
作者：
Kohanski MA;Dwyer DJ;Wierzbowski J;Cottarel G;Collins JJ
通讯作者：
Collins JJ
影响因子：
64.5
作者：
Kohanski, Michael A.;Dwyer, Daniel J.;Collins, James J.
通讯作者：
Collins, James J.
影响因子：
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作者：
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通讯作者：
Anjum, Muna F.
影响因子：
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