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RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and 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 showed that such coordination could be hijacked by ribosome antibiotics to trigger secondary damage predominantly contributing to their efficacy, via a yet overlooked reverse-central-dogma pathway. Through the utilization of a self-establishing transcription dynamics profiling method, complemented by genetic and biochemical approaches, we unveil that the disruption of transcription-translation coupling leads to premature stalling of RNA polymerase (RNAP) at genome scale, subsequently triggering extensive genomic instability. Moreover, a distinct subpopulation exhibits hyperactivation of the SOS response, facilitating an inducible evolutionary path towards genetic resistance characterized by a unique mutation spectrum. Our findings reveal the emergence of secondary drug damage resulting from network disorder, and establish a framework to understand antibiotic efficacy and induced mutagenesis from a systems biology perspective.

ORGANISM(S): Escherichia coli

PROVIDER: GSE234254 | GEO | 2023/12/24

REPOSITORIES: GEO

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RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution

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