Fumarate and nitrate reduction regulator (FNR) modulates hypermucoviscosity and virulence in hypervirulent through anaerobic adaptation.

Hypervirulent (hvKP), a pathogen responsible for severe invasive infections, exhibits a hypermucoviscosity (HMV) phenotype that is closely associated with its virulence. While fumarate and nitrate reduction regulator (FNR), a global transcription regulator, is critical for bacterial adaptation to hypoxic conditions, its role in hvKP pathogenicity remains unexplored. This study demonstrates that FNR modulates the HMV phenotype and virulence of the hvKP strain NTUH-K2044 under anaerobic conditions. Through targeted deletion and complementation of the gene, combined with phenotypic, molecular, cellular, and animal infection assays, we show that FNR positively regulates the HMV phenotype. Notably, this regulation is independent of several genes previously implicated in HMV formation, including , , (), , and . In the absence of , the HMV phenotype was abolished, while the transcript levels of these genes increased significantly, suggesting a compensatory or indirect regulatory mechanism that warrants further investigation. Functionally, FNR-mediated HMV enhanced bacterial resistance to phagocytosis and serum killing while suppressing host colonization features such as fimbriae formation, biofilm production, and epithelial cell adhesion. In animal infection models, FNR also contributed positively to hvKP virulence. These findings highlight the role of FNR in regulating the HMV phenotype and virulence in hvKP, facilitating host adaptation and immune evasion. Targeting FNR may thus represent a promising strategy for the development of novel therapeutics.