Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria.
Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria.
复制标题
Facile Accelerated Specific Therapeutic（FAST）平台开发反义疗法来对抗多重耐药细菌。
DOI：
10.1038/s42003-021-01856-1
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发表时间：
2021-03-12
影响因子：
5.9
通讯作者：
Chatterjee A
中科院分区：
文献类型：
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作者：
Eller KA;Aunins TR;Courtney CM;Campos JK;Otoupal PB;Erickson KE;Madinger NE;Chatterjee A
多药耐药（MDR）细菌对全球健康构成严重关切，由于缺乏新的治疗方法和对策平台来对抗疫情或抗生素耐药性，这种情况一直存在。为了解决这个问题，我们开发了一种快速加速特异性治疗（FAST）平台，可以在一周内开发出针对MDR细菌的有效肽核酸（PNA）疗法。我们的FAST平台使用生物信息学工具箱设计针对细菌非传统途径/基因的序列特异性PNA，然后对选定的PNA进行原位合成，验证和功效测试。作为概念验证，针对5种MDR临床分离株检测了这些PNA：碳青霉烯类耐药大肠埃希菌、超广谱β-内酰胺酶肺炎克雷伯菌、携带金属β-内酰胺酶-1的肺炎克雷伯菌新德里和MDR肠道沙门氏菌。PNA对82%的处理显示出显著的生长抑制，其中近18%的处理导致超过97%的减少。此外，尽管存在同源耐药基因，这些PNA仍能够增强临床分离株中的抗生素活性。最后，FAST平台提供了一种新的递送方法，通过重新利用细菌III型分泌系统结合杀伤开关来克服PNA向哺乳动物细胞中的有限转运，该杀伤开关可有效消除人类上皮细胞中99.6%的细胞内沙门氏菌感染。埃勒等人开发了一种利用肽核酸（PNA）靶向MDR细菌病原体的反义治疗剂的简易加速特异性治疗（FAST）平台。该平台基于生物信息学工具箱设计了物种和/或序列特异性PNAS，并通过重新利用细菌III型分泌系统与杀伤开关来克服PNA向哺乳动物细胞中的有限转运，从而提供了一种新的递送方法。
Multidrug-resistant (MDR) bacteria pose a grave concern to global health, which is perpetuated by a lack of new treatments and countermeasure platforms to combat outbreaks or antibiotic resistance. To address this, we have developed a Facile Accelerated Specific Therapeutic (FAST) platform that can develop effective peptide nucleic acid (PNA) therapies against MDR bacteria within a week. Our FAST platform uses a bioinformatics toolbox to design sequence-specific PNAs targeting non-traditional pathways/genes of bacteria, then performs in-situ synthesis, validation, and efficacy testing of selected PNAs. As a proof of concept, these PNAs were tested against five MDR clinical isolates: carbapenem-resistant Escherichia coli, extended-spectrum beta-lactamase Klebsiella pneumoniae, New Delhi Metallo-beta-lactamase-1 carrying Klebsiella pneumoniae, and MDR Salmonella enterica. PNAs showed significant growth inhibition for 82% of treatments, with nearly 18% of treatments leading to greater than 97% decrease. Further, these PNAs are capable of potentiating antibiotic activity in the clinical isolates despite presence of cognate resistance genes. Finally, the FAST platform offers a novel delivery approach to overcome limited transport of PNAs into mammalian cells by repurposing the bacterial Type III secretion system in conjunction with a kill switch that is effective at eliminating 99.6% of an intracellular Salmonella infection in human epithelial cells. Eller et al. develop a Facile Accelerated Specific Therapeutic (FAST) platform of antisense therapeutics that targets MDR bacterial pathogens with peptide nucleic acids (PNAs). This platform designs species and/or sequence specific PNAS based on a bioinformatics toolbox and offers a new delivery approach by repurposing the bacterial Type III secretion system in conjunction with a kill switch to overcome limited transport of PNAs into mammalian cells.