美国洛克菲勒大学Jeremy M. Rock和威尔康奈尔医学院Dirk Schnappinger小组合作利用全基因组基因表达调控揭示了结核分枝杆菌 (Mtb)的脆弱性。该项研究成果在线发表在2021年7月22日出版的《细胞》上。
研究人员开发了一种基于CRISPR干扰的功能基因组学方法，以系统地确定结核分枝杆菌中的基因表达并监测细菌的适应性。研究在各种过程中确定了具有高度脆弱性的基因，包括未知的药物新靶点。同时，研究确定了必需的基本基因，这可能解释了药物研发失败的原因。正常和高毒力Mtb分离株之间的脆弱性比较揭示了脆弱性的不完全保护，并且不同的脆弱性可以预测不同的抗菌敏感性。该研究结果定量定义了基本的细菌过程，并发现了具有药物开发潜能的新靶点。
据介绍，抗菌药物靶向必需基因，但很少能实现完全抑菌的目的。因此，利用传统遗传方法得到的对必需基因有或无效的靶点并非是最有吸引力的细菌靶标：因为抑制作用不足反而导致细菌适应性增加。相比之下，基因“脆弱性”是一种连续的、可量化的特征，它把基因的抑制程度与对细菌适应性的影响联系起来。
附：英文原文
Title: Genome-wide gene expression tuning reveals diverse vulnerabilities of M. tuberculosis
Author: Barbara Bosch, Michael A. DeJesus, Nicholas C. Poulton, Wenzhu Zhang, Curtis A. Engelhart, Anisha Zaveri, Sophie Lavalette, Nadine Ruecker, Carolina Trujillo, Joshua B. Wallach, Shuqi Li, Sabine Ehrt, Brian T. Chait, Dirk Schnappinger, Jeremy M. Rock
Issue&Volume: 2021-07-22
Abstract: Antibacterial agents target the products of essential genes but rarely achieve complete target inhibition. Thus, the all-or-none definition of essentiality afforded by traditional genetic approaches fails to discern the most attractive bacterial targets: those whose incomplete inhibition results in major fitness costs. In contrast, gene “vulnerability” is a continuous, quantifiable trait that relates the magnitude of gene inhibition to the effect on bacterial fitness. We developed a CRISPR interference-based functional genomics method to systematically titrate gene expression in Mycobacterium tuberculosis (Mtb) and monitor fitness outcomes. We identified highly vulnerable genes in various processes, including novel targets unexplored for drug discovery. Equally important, we identified invulnerable essential genes, potentially explaining failed drug discovery efforts. Comparison of vulnerability between the reference and a hypervirulent Mtb isolate revealed incomplete conservation of vulnerability and that differential vulnerability can predict differential antibacterial susceptibility. Our results quantitatively redefine essential bacterial processes and identify high-value targets for drug development.
DOI: 10.1016/j.cell.2021.06.033
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00824-2