迈向广谱治疗的步骤：发现存在于多种人类病原体中的毒力相关基因。
Steps toward broad-spectrum therapeutics: discovering virulence-associated genes present in diverse human pathogens.
机构信息
Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM, USA.
出版信息
BMC Genomics. 2009 Oct 29;10:501. doi: 10.1186/1471-2164-10-501.
BACKGROUND
New and improved antimicrobial countermeasures are urgently needed to counteract increased resistance to existing antimicrobial treatments and to combat currently untreatable or new emerging infectious diseases. We demonstrate that computational comparative genomics, together with experimental screening, can identify potential generic (i.e., conserved across multiple pathogen species) and novel virulence-associated genes that may serve as targets for broad-spectrum countermeasures.
RESULTS
Using phylogenetic profiles of protein clusters from completed microbial genome sequences, we identified seventeen protein candidates that are common to diverse human pathogens and absent or uncommon in non-pathogens. Mutants of 13 of these candidates were successfully generated in Yersinia pseudotuberculosis and the potential role of the proteins in virulence was assayed in an animal model. Six candidate proteins are suggested to be involved in the virulence of Y. pseudotuberculosis, none of which have previously been implicated in the virulence of Y. pseudotuberculosis and three have no record of involvement in the virulence of any bacteria.
CONCLUSION
This work demonstrates a strategy for the identification of potential virulence factors that are conserved across a number of human pathogenic bacterial species, confirming the usefulness of this tool.
背景
为了对抗现有抗菌疗法耐药性的增加和目前无法治疗或新出现的传染病，急需新的、改进的抗菌对策。我们证明，计算比较基因组学与实验筛选相结合，可以识别潜在的通用（即在多种病原体物种中保守）和新型与毒力相关的基因，这些基因可能成为广谱对策的靶标。
结果
我们使用来自已完成微生物基因组序列的蛋白质聚类的系统发育图谱，鉴定了十七种在不同人类病原体中常见而在非病原体中缺失或不常见的蛋白质候选物。成功地在假结核耶尔森菌中生成了这 13 个候选物的突变体，并在动物模型中检测了这些蛋白质在毒力中的潜在作用。有 6 种候选蛋白被认为参与了假结核耶尔森菌的毒力，其中没有一种以前与假结核耶尔森菌的毒力有关，有三种以前没有涉及任何细菌的毒力。
结论
这项工作展示了一种鉴定在多种人类致病细菌物种中保守的潜在毒力因子的策略，证实了这种工具的有用性。
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