Model-guided Identification of Synthetic Lethal Genes for Drug Target Development

描述（由申请人提供）：过去几十年来，由对至少一种抗生素具有抗药性的细菌引起的感染数量急剧增加。同一时期，批准临床使用的新抗生素数量也出现了同样惊人的下降。这两种趋势背后的一个原因是，当前的基因组和其他分析在细菌内产生的新的单一药物靶标很少，令人失望，这种情况需要重新努力开发新的药物靶标识别策略，例如开发联合疗法的合理方法。我们在这里提出了一种这样的方法：部署基因组规模的代谢计算机模型和系统生物学的其他工具，以识别致病性肠杆菌代谢网络内的合成致死和合成患病基因对。然后通过在大肠杆菌和鼠伤寒沙门氏菌中构建假定对来对模型预测进行实验测试。然后，确认对两种生物体具有综合致死性的配对将进行虚拟和高通量筛选，以鉴定能够抑制生长或杀死多种肠杆菌成员的广谱双组分制剂。该计划将因此实现两个重要目标：建立基于系统生物学的代谢模型，作为合理、全面和公正地发现组合药物开发靶标的一种方式，并确定特定的小分子对，用于可能针对一类重要人类病原体的药物开发。

DESCRIPTION (provided by applicant): The past several decades have seen an alarming rise in the number of infections caused by bacteria resistant to at least one antibiotic. During the same period, there has been an equally alarming decline in the number of new antibiotics receiving approval for clinical use. One reason underlying both trends is that current genomic and other analyses have produced disappointingly few new single drug targets within bacteria, a situation that calls for renewed efforts to develop novel drug target identification strategies such as rational ways to develop combination therapies. We propose one such method here: to deploy genome-scale in silico models of metabolism and other tools from systems biology to identify synthetic lethal and synthetic sick gene pairs within the metabolic networks of pathogenic Enterobacteria. Model predictions would then be tested experimentally by constructing putative pairs in Escherichia coli and Salmonella enterica serovar Typhimurium. Pairs confirmed to be synthetically lethal in both organisms would then be subjected to virtual and high-throughput screening to identify broad-spectrum two-component formulations which inhibit growth or kill multiple members of Enterobacteria. This program would achieve two important goals as a result: to establish systems biology-based metabolic models as one way to uncover - rationally, comprehensively, and in an unbiased manner - targets for combinatorial drug development, and to identify specific pairs of small molecules for possible drug development against an important class of human pathogens.