美国洛克菲勒大学Jeremy M. Rock和Elizabeth A. Campbell共同合作，近期取得重要工作进展。他们研究提出，NusG的补偿性演化可以提高耐药性结核杆菌的适应性。相关研究成果2024年3月20日在线发表于《自然》杂志上。

据介绍，耐药细菌正在成为一种全球威胁，尽管它们的健康状况往往不如它们对药物敏感的祖先。

研究人员试图定义驱动或缓冲细菌病原体结核分枝杆菌（Mtb）中利福平耐药性（RifR）适应度成本的机制。利福平抑制RNA聚合酶（RNAP），是现代短期结核病治疗的基石。

然而，在因耐药细菌导致的死亡病例中，RifR Mtb占四分之一。研究人员采用比较功能基因组学方法来定义RifR-Mtb中不同易受CRISPR干扰（CRISPRi）抑制的过程。在其它研究中，研究人员发现普遍保守的转录因子NusG对RifR-Mtb的适应度至关重要。与其在大肠杆菌中的作用相反，Mtb-NusG具有通过与RNAP和DNA的不同接触介导的重要RNAP前暂停功能。研究人员发现这种支持暂停的NusG–RNAP接口在临床RifR-Mtb分离株中处于阳性选择之下。NusG–RNAP界面的突变降低了前暂停活性并增加了RifR-Mtb的适应度。

总之，这些结果将过度的RNAP暂停定义为一种分子机制，它驱动了Mtb中RifR的适应性成本，确定了一种新的补偿机制来克服这种成本，提出了加剧适应性代价的合理方法，而且从更广泛的意义上讲，可以为开发药物组合以减缓Mtb中RifR的演化提供新的治疗方法。

附： 英文原文

Title: Compensatory evolution in NusG improves fitness of drug-resistant M. tuberculosis

Author: Eckartt, Kathryn A., Delbeau, Madeleine, Munsamy-Govender, Vanisha, DeJesus, Michael A., Azadian, Zachary A., Reddy, Abhijna K., Chandanani, Joshua, Poulton, Nicholas C., Quiones-Garcia, Stefany, Bosch, Barbara, Landick, Robert, Campbell, Elizabeth A., Rock, Jeremy M.

Issue&Volume: 2024-03-20

Abstract: Drug-resistant bacteria are emerging as a global threat, despite frequently being less fit than their drug-susceptible ancestors1,2,3,4,5,6,7,8. Here we sought to define the mechanisms that drive or buffer the fitness cost of rifampicin resistance (RifR) in the bacterial pathogen Mycobacterium tuberculosis (Mtb). Rifampicin inhibits RNA polymerase (RNAP) and is a cornerstone of modern short-course tuberculosis therapy9,10. However, RifR Mtb accounts for one-quarter of all deaths due to drug-resistant bacteria11,12. We took a comparative functional genomics approach to define processes that are differentially vulnerable to CRISPR interference (CRISPRi) inhibition in RifR Mtb. Among other hits, we found that the universally conserved transcription factor NusG is crucial for the fitness of RifR Mtb. In contrast to its role in Escherichia coli, Mtb NusG has an essential RNAP pro-pausing function mediated by distinct contacts with RNAP and the DNA13. We find this pro-pausing NusG–RNAP interface to be under positive selection in clinical RifR Mtb isolates. Mutations in the NusG–RNAP interface reduce pro-pausing activity and increase fitness of RifR Mtb. Collectively, these results define excessive RNAP pausing as a molecular mechanism that drives the fitness cost of RifR in Mtb, identify a new mechanism of compensation to overcome this cost, suggest rational approaches to exacerbate the fitness cost, and, more broadly, could inform new therapeutic approaches to develop drug combinations to slow the evolution of RifR in Mtb.

DOI: 10.1038/s41586-024-07206-5

Source: https://www.nature.com/articles/s41586-024-07206-5