Mutation of RNA polymerase sigma factor (RpoD) confers broad‑spectrum antimicrobial tolerance through global transcriptional reprogramming

As a result, genes involved in ribosome biogenesis, purine and pyrimidine metabolism, ATP synthesis, and other core metabolic processes were down‑regulated, while ROS‑detoxifying genes (e.g., katEG and sodAB) were up‑regulated, thereby suppressing the accumulation of toxic metabolites such as ROS and enhancing antioxidant capacity when cells were treated with diverse antimicrobials. Both activities suppress and/or delay the lethal action of antimicrobials.

Tolerance mediated by mutations in the PTS‑cAMP‑Crp pathway were suppressed by over-expression of rpoD, consistent with a transcription‑regulated pathway downstream from PTS‑cAMP‑Crp. These findings provide a conceptual foundation for understanding bacterial tolerance and developing new strategies to combat bacterial tolerance and resistance to antimicrobial therapy.