A Pipeline for Screening Small Molecules with Growth Inhibitory Activity against Burkholderia cenocepacia.
A Pipeline for Screening Small Molecules with Growth Inhibitory Activity against Burkholderia cenocepacia.
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DOI：
10.1371/journal.pone.0128587
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Cardona ST
中科院分区：
文献类型：
--
作者：
Selin C;Stietz MS;Blanchard JE;Gehrke SS;Bernard S;Hall DG;Brown ED;Cardona ST
在囊性纤维化患者中，洋葱伯克霍尔德氏菌复合体（Bcc）的感染很难根除，这是因为Bcc对大多数可用抗生素具有内在耐药性，并且在抗生素治疗期间出现了多种抗生素耐药菌株。在这项工作中，我们使用了一个全细胞为基础的分析，以筛选不同的收集的小分子的生长抑制剂的相关菌株的Bcc，B。新洋葱K56-2。初步筛选使用96孔板形式的细菌生长，并在30，259种化合物中鉴定出206种主要活性物质。从100个以前没有抗菌活性记录的化合物中进行二次筛选和数据挖掘，选择了进一步分析的Bce生物活性物质。本实验采用C. elegans用于优先选择具有更好机会作为潜在BCC抗菌药物进一步研究的化合物。这种高通量筛选，沿着体外和体内分析，突出了这种实验方法的实用性，以快速鉴定生物活性物质作为抗菌药物发现的起点。
Infections with the bacteria Burkholderia cepacia complex (Bcc) are very difficult to eradicate in cystic fibrosis patients due the intrinsic resistance of Bcc to most available antibiotics and the emergence of multiple antibiotic resistant strains during antibiotic treatment. In this work, we used a whole-cell based assay to screen a diverse collection of small molecules for growth inhibitors of a relevant strain of Bcc, B. cenocepacia K56-2. The primary screen used bacterial growth in 96-well plate format and identified 206 primary actives among 30,259 compounds. From 100 compounds with no previous record of antibacterial activity secondary screening and data mining selected a total of Bce bioactives that were further analyzed. An experimental pipeline, evaluating in vitro antibacterial and antibiofilm activity, toxicity and in vivo antibacterial activity using C. elegans was used for prioritizing compounds with better chances to be further investigated as potential Bcc antibacterial drugs. This high throughput screen, along with the in vitro and in vivo analysis highlights the utility of this experimental method to quickly identify bioactives as a starting point of antibacterial drug discovery.
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