Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, New York, United States of America.
PLoS Pathog. 2019 Sep 19;15(9):e1007975. doi: 10.1371/journal.ppat.1007975. eCollection 2019 Sep.
Stewart Cole and colleagues determined the complete genome sequence of Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), in 1998 [1]. This was a landmark achievement that heralded a new age in TB drug discovery. With the genome sequence in hand, drug discoverers suddenly had thousands of new potential targets to explore. But the excitement has since faded [2]. It is unquestioned that genomics has transformed our understanding of the biology of this pathogen. However, the expectation that the Mtb genome sequence would rapidly lead to new therapeutic interventions remains unfulfilled [3]. One of the (many) reasons for this unrealized potential is that our tools to systematically interrogate the Mtb genome and its drug targets-so-called functional genomics-have been limited. In this Pearl, I argue that the recent development of robust CRISPR-based genetics in Mtb [4] overcomes many prior limitations and holds the potential to close the gap between genomics and TB drug discovery.
1998 年，Stewart Cole 及其同事确定了结核分枝杆菌（Mtb）——结核病（TB）病原体的全基因组序列[1]。这是一项具有里程碑意义的成就，标志着 TB 药物发现的新时代的到来。随着基因组序列的出现，药物发现者突然有了数千个新的潜在靶点可供探索。但这种兴奋感后来逐渐消退了[2]。毫无疑问，基因组学已经改变了我们对这种病原体生物学的理解。然而，Mt b 基因组序列将迅速带来新的治疗干预的预期尚未实现[3]。造成这种未实现的潜力的原因之一（其中许多原因）是，我们用于系统研究 Mtb 基因组及其药物靶点的工具——所谓的功能基因组学——受到限制。在这篇 Pearl 中，我认为，最近在 Mtb 中发展起来的稳健的基于 CRISPR 的遗传学[4]克服了许多先前的限制，并有可能弥合基因组学和 TB 药物发现之间的差距。
