Nickel-Dependent Urease Enables Staphylococcus aureus Persistence in Acidic Environments Original paper

What was studied?

This study investigated urease function in Staphylococcus aureus, focusing on how this enzyme supports pH homeostasis and microbial survival during acidic stress—a key topic for a microbiome signatures database because S. aureus occupies acidic host niches and interacts metabolically with host-derived urea. The authors explored how urease activity contributes to maintaining intracellular pH, how its transcription is regulated, and whether endogenous urea derived from arginine metabolism contributes to nitrogen use or acid resistance. The work also examined urease-mediated survival during a chronic murine kidney infection, a setting with high urea concentration and low pH. Figures throughout the paper illustrate these dynamics; for example, the growth and pH curves show ammonia generation driving extracellular alkalinization under glucose-induced acetate stress, and the chronic infection data demonstrate urease-dependent persistence in vivo.

Who was studied?

The research used Staphylococcus aureus strain JE2 and various mutant derivatives, including urease-null strains and regulatory mutants (ΔccpA, Δagr, ΔcodY). Laboratory analyses were performed in vitro using glucose-rich media, chemically defined media, and assays monitoring metabolites, transcription, and viability. For the in vivo component, male and female C57BL/6 mice were used in a bacteremia model to assess kidney colonization. This dual organism approach—bacterial strains plus mammalian hosts—allowed the authors to connect molecular mechanisms of urease function with physiological relevance in a living system.

Most important findings

The study demonstrated that urease is a key acid-resistance mechanism in Staphylococcus aureus, enabling survival by converting urea into ammonia, which buffers intracellular pH. Wild-type strains maintained viability under acetic-acid stress, while urease-deficient mutants showed sharp CFU loss. Regulation of the urease operon depends on major global regulators—CcpA and Agr activate transcription, whereas CodY represses it—positioning urease within core metabolic sensing pathways. The authors also confirmed that arginine-derived urea is excreted rather than metabolized under neutral pH, indicating urease is not used for nitrogen assimilation outside acidic stress conditions. In vivo, urease proved essential for kidney persistence, as shows progressive clearance of urease-null mutants, with no major differences in leukocyte infiltration, supporting a metabolic rather than immune-driven mechanism.

Key implications

This work shows that urease enables S. aureus to withstand acidic, urea-rich conditions by stabilizing pH and preventing reactive oxygen species accumulation. In microbial ecology terms, urease represents a metabolic signature enabling niche persistence, particularly in host tissues with steep pH and urea gradients. For clinical microbiology, the findings elevate urease as a potential target for disrupting persistence in chronic infections—including kidney reservoirs that seed metastatic disease. Additionally, urease’s tight regulation by global metabolic circuits illustrates how nutrient status and environmental pH converge to drive virulence-associated traits in S. aureus, providing valuable context for microbiome-driven pathogen profiling.

Citation

Zhou C, Bhinderwala F, Lehman MK, Thomas VC, Chaudhari SS, Yamada KJ, et al. Urease is an essential component of the acid response network of Staphylococcus aureus and is required for a persistent murine kidney infection.PLoS Pathog. 2019;15(1):e1007538