A phosphorylation signal activates genome-wide transcriptional control by BfmR, the global regulator of Acinetobacter resistance and virulence.

Summary

This mechanistic study shows that phosphorylation activates BfmR to dimerize, expand genome-wide binding, and directly regulate 303 genes involved in envelope biogenesis and pilus repression, among others. Phospho-BfmR is required for antibiotic resistance and sepsis development in vivo, positioning the BfmS-BfmR system as a therapeutic target.

Key Findings

• Phosphorylation is required for BfmR-mediated gene regulation, antibiotic resistance, and sepsis development in vivo.
• Phosphorylation induces BfmR dimerization and increases target DNA affinity, expanding genome-wide binding sites.
• BfmR directly regulates 303 genes including capsule, peptidoglycan, and outer membrane biogenesis (activation) and pilus biogenesis (repression).
• A direct repeat DNA motif underlies BfmR recognition and is widespread in promoters; BfmR also controls non-coding sRNAs.

Clinical Implications

While preclinical, the findings nominate the BfmS-BfmR signaling axis as a drug target to attenuate Acinetobacter virulence and resistance, potentially reducing sepsis severity and improving antibiotic effectiveness.

Limitations

• Preclinical bacterial and murine models may not fully capture human infection complexity
• No therapeutic inhibitor of BfmS-BfmR tested for efficacy

Future Directions

Develop and test small-molecule inhibitors of BfmS-BfmR signaling; validate regulon and phenotypes across clinical isolates and infection models; delineate host-pathogen interactions influenced by BfmR.