A reverse-central-dogma pathway underlies ribosome-antibiotic efficacy and accelerates resistance evolution

doi:10.1101/2023.08.03.551753

	A reverse-central-dogma pathway underlies ribosome-antibiotic efficacy and accelerates resistance evolution
	Zheng, Yayun 1; Chai, Ruochen 1; Xu, Zeqi 1; He, Yihui 1; Shen, Ping 1; Liu, Jintao 1,2; Wang, Tianmin3
	2023-08-04
状态	已发表
摘要	In bacteria, the precise coordination of DNA replication, transcription and translation is mediated by dynamic interactions among the corresponding macromolecular machineries, playing a pivotal role in maintaining cellular homeostasis. Here we show that such coordination is hijacked by ribosome antibiotics to trigger secondary damage that predominantly contributes to their efficacy. Specifically, through developing a transcription dynamics profiling method, complemented by genetic and biochemical approaches, we unveil that translation inhibition disrupts transcription translation coupling, leading to premature stalling of RNA polymerase (RNAP) at genome scale, which subsequently triggers extensive genomic instability. Moreover, mutagenic repairment of genomic lesions is mediated by heterogenous hyperactivation of SOS response, facilitating an inducible evolutionary path towards genetic resistance characterized by a unique mutation spectrum. Our findings thereby reveal a yet overlooked reverse-central-dogma pathway underlying actions of ribosome inhibitors, and establish a framework to understand antibiotic efficacy and induced mutagenesis through network disorder.
语种	英语
DOI	10.1101/2023.08.03.551753
相关网址	查看原文
出处	bioRxiv
收录类别	PPRN.PPRN
WOS记录号	PPRN:74236957
WOS类目	Microbiology
资助项目	Tsinghua-Peking Center for Life Sciences[32100071]
文献类型	预印本
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/381286
专题	生命科学与技术学院生命科学与技术学院_PI研究组_王天民组
通讯作者	Liu, Jintao; Wang, Tianmin
作者单位	1.Tsinghua Univ, Ctr Infect Dis Res, Sch Med, Beijing 100084, Peoples R China 2.Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Zheng, Yayun,Chai, Ruochen,Xu, Zeqi,et al. A reverse-central-dogma pathway underlies ribosome-antibiotic efficacy and accelerates resistance evolution. 2023.