Payne D J, Wallis N G, Gentry D R, Rosenberg M
Anti-infectives Research (UP1345), SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426-0989, USA.
Curr Opin Drug Discov Devel. 2000 Mar;3(2):177-90.
Antibiotic discovery has remained primarily focused on improving versions of existing classes of antibiotics which work on a limited set of bacterial targets. In addition, the characterization of these targets has focused almost entirely on Escherichia coli homologs. The advancing problems associated with resistant pathogens has driven a critical need for the discovery of new classes of antibiotics which will target novel bacterial functions required for viability and pathogenicity. Recent advances in DNA sequencing technology have now made it possible to elucidate the entire genomes of pathogenic bacteria. Comparative analysis of these genome sequences, driven by advancements in the availability of bioinformatic tools, is dramatically increasing our ability to interrogate the spectrum and selectivity of novel antibacterial target areas. In this review, we present an update on the antibiotic target areas of tRNA synthetases, two-component signal transduction systems, peptidoglycan biosynthesis, fatty acid biosynthesis and chorismate biosynthesis. We illustrate how the availability of genomes from a range of clinically important pathogens has enabled valid considerations of the limitations and advantages of particular targets based on their predicted spectrum and selectivity. Furthermore, we demonstrate how genomics is facilitating the characterization of targets from relevant pathogens and how these data, coupled with genomic-based technologies, provide new approaches for drug discovery.
抗生素的发现主要集中在改进现有抗生素类别，这些抗生素作用于有限的一组细菌靶点。此外，这些靶点的特性几乎完全集中在大肠杆菌的同源物上。与耐药病原体相关的日益严重的问题迫切需要发现新型抗生素，这些抗生素将针对生存能力和致病性所需的新细菌功能。DNA测序技术的最新进展现已使阐明病原菌的全基因组成为可能。在生物信息学工具可用性提高的推动下，对这些基因组序列的比较分析极大地增强了我们探究新型抗菌靶点区域的范围和选择性的能力。在本综述中，我们介绍了关于tRNA合成酶、双组分信号转导系统、肽聚糖生物合成、脂肪酸生物合成和分支酸生物合成的抗生素靶点区域的最新情况。我们阐述了一系列临床重要病原体的基因组可用性如何基于其预测的范围和选择性，使人们能够有效考虑特定靶点的局限性和优势。此外，我们展示了基因组学如何促进对相关病原体靶点的特性描述，以及这些数据与基于基因组的技术如何为药物发现提供新方法。
