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

Abstract

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.