Becker Daniel, Selbach Matthias, Rollenhagen Claudia, Ballmaier Matthias, Meyer Thomas F, Mann Matthias, Bumann Dirk
Max-Planck-Institute for Infection Biology, Department of Molecular Biology, D-10117 Berlin, Germany.
Nature. 2006 Mar 16;440(7082):303-7. doi: 10.1038/nature04616.
New antibiotics are urgently needed to control infectious diseases. Metabolic enzymes could represent attractive targets for such antibiotics, but in vivo target validation is largely lacking. Here we have obtained in vivo information about over 700 Salmonella enterica enzymes from network analysis of mutant phenotypes, genome comparisons and Salmonella proteomes from infected mice. Over 400 of these enzymes are non-essential for Salmonella virulence, reflecting extensive metabolic redundancies and access to surprisingly diverse host nutrients. The essential enzymes identified were almost exclusively associated with a small subgroup of pathways, enabling us to perform a nearly exhaustive screen. Sixty-four enzymes identified as essential in Salmonella are conserved in other important human pathogens, but almost all belong to metabolic pathways that are inhibited by current antibiotics or that have previously been considered for antimicrobial development. Our comprehensive in vivo analysis thus suggests a shortage of new metabolic targets for broad-spectrum antibiotics, and draws attention to some previously known but unexploited targets.
控制传染病迫切需要新型抗生素。代谢酶可能是这类抗生素颇具吸引力的靶点，但体内靶点验证在很大程度上尚属欠缺。在此，我们通过对突变体表型进行网络分析、开展基因组比较以及分析感染小鼠体内的沙门氏菌蛋白质组，获得了有关700多种肠炎沙门氏菌酶的体内信息。其中400多种酶对沙门氏菌的毒力并非必需，这反映出广泛的代谢冗余以及沙门氏菌能够获取惊人多样的宿主营养物质。所鉴定出的必需酶几乎完全与一小部分代谢途径相关，这使我们能够进行近乎详尽无遗的筛选。在沙门氏菌中被鉴定为必需的64种酶在其他重要的人类病原体中保守存在，但几乎所有这些酶都属于目前抗生素所抑制的代谢途径，或者此前已被考虑用于抗菌药物研发的代谢途径。因此，我们全面的体内分析表明，广谱抗生素缺乏新的代谢靶点，并使人们关注到一些先前已知但未被开发利用的靶点。
