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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy
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Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy

机译：工程化噬菌体靶向基因网络作为抗生素治疗的佐剂

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Antimicrobial drug development is increasingly lagging behind the evolution of antibiotic resistance, and as a result, there is a pressing need for new antibacterial therapies that can be readily designed and implemented. In this work, we engineered bacteriophage to overexpress proteins and attack gene networks that are not directly targeted by antibiotics. We show that suppressing the SOS network in Escherichia coli with engineered bacteriophage enhances killing by quinolones by several orders of magnitude in vitro and significantly increases survival of infected mice in vivo. In addition, we demonstrate that engineered bacteriophage can enhance the killing of antibiotic-resistant bacteria, persister cells, and biofilm cells, reduce the number of antibiotic-resistant bacteria that arise from an antibiotic-treated population, and act as a strong adjuvant for other bactericidal antibiotics (e.g., aminoglycosides and β-lactams). Furthermore, we show that engineering bacteriophage to target non-SOS gene networks and to overexpress multiple factors also can produce effective antibiotic adjuvants. This work establishes a synthetic biology platform for the rapid translation and integration of identified targets into effective antibiotic adjuvants.
机译：抗菌药物的开发越来越落后于抗生素耐药性的发展，因此，迫切需要一种易于设计和实施的新型抗菌疗法。在这项工作中，我们设计了噬菌体以过度表达蛋白质并攻击未直接由抗生素靶向的基因网络。我们显示，用工程噬菌体抑制大肠杆菌中的SOS网络可增强喹诺酮类药物在体外的杀伤力，并在体外增加了几个数量级。此外，我们证明了工程化的噬菌体可以增强对抗生素抗性细菌，持久性细胞和生物膜细胞的杀灭，减少由抗生素治疗人群产生的抗生素抗性细菌的数量，并可以作为其他细菌的强佐剂杀菌抗生素（例如氨基糖苷类和β-内酰胺类）。此外，我们表明工程化噬菌体以非SOS基因网络为目标并过表达多种因素也可以产生有效的抗生素佐剂。这项工作建立了一个合成生物学平台，用于将已鉴定的靶标快速翻译和整合到有效的抗生素佐剂中。

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