A genomics based strategy for the discovery and study of new signaling systems...

小分子在细菌感染的建立和传播中都扮演着重要的角色。 尽管在控制下生长的细菌病原体产生的小分子的特征 实验室的条件导致发现了许多重要的信号分子和毒素， 实验室发酵条件不能代表感染的生长条件 发生。因此，基于实验室的发酵研究不太可能提供完整的 细菌病原体在感染过程中使用的分子谱系。神秘的小分子生物合成 基因簇，似乎不编码任何已知代谢物的生物合成的基因簇，是 通常在已测序的细菌基因组中发现。这些神秘的路径代表着路径池 从中将在细菌病原体中发现额外的信号系统和毒素。中概述的工作 这项提议将提供访问以前未知的分子的途径，这些分子由神秘的生物合成材料编码 在生物防御相关细菌病原体的基因组中发现的途径。详细分析了 许多与生物防御相关的病原体的基因组表明，它们含有许多以前未知的 基因簇可能编码生物合成，到目前为止，尚不确定的小分子。基因组学 我们用来发现小分子的方法应该会产生更完整的 描述用于生物防御的小分子信号和毒素的复杂网络 相关的细菌病原体；因此，为如何最好地扰乱 细菌感染的建立和繁殖。

Small molecules play important roles in both the establishment and propagation of bacterial infections. Although the characterization of small molecules produced by bacterial pathogens grown under controlled conditions in the laboratory has led to the discovery of many important signaling molecules and toxins, laboratory fermentation conditions are not representative of the growth conditions under which an infection occurs. Laboratory based fermentation studies are therefore unlikely to have provided access to the full repertoire of molecules used by bacterial pathogens during an infection. Cryptic small molecule biosynthetic gene clusters, gene clusters that do not appear to encode the biosynthesis of any known metabolites, are routinely found in sequenced bacterial genomes. These cryptic pathways represent the pool of pathways from which additional signaling systems and toxins will be found in bacterial pathogens. The work outlined in this proposal will provide access to previously unknown molecules encoded by the cryptic biosynthetic pathways found in the genomes of biodefense relevant bacterial pathogens. A detailed analysis of the genomes of many biodefense relevant pathogens suggests that they contain numerous previously unknown gene clusters that likely code for the biosynthesis of, as yet, unidentified small molecules. The genomics based approaches that we are using for the discovery of small molecules should result in a more complete description of the complex networks of small molecule signals and toxins that are used by biodefense relevant bacterial pathogens; and as a result, provide novel insights into how best to disrupt key steps in the establishment and propagation of bacterial infections.