Abstract
Staphylococcus aureus causes acute and chronic infections resulting in significant morbidity. Urease, an enzyme that generates NH3 and CO2 from urea, is key to pH homeostasis in bacterial pathogens under acidic stress and nitrogen limitation. However, the function of urease in S. aureus niche colonization and nitrogen metabolism has not been extensively studied. We discovered that urease is essential for pH homeostasis and viability in urea-rich environments under weak acid stress. The regulation of urease transcription by CcpA, Agr, and CodY was identified in this study, implying a complex network that controls urease expression in response to changes in metabolic flux. In addition, it was determined that the endogenous urea derived from arginine is not a significant contributor to the intracellular nitrogen pool in non-acidic conditions. Furthermore, we found that during a murine chronic renal infection, urease facilitates S. aureus persistence by promoting bacterial fitness in the low-pH, urea-rich kidney. Overall, our study establishes that urease in S. aureus is not only a primary component of the acid response network but also an important factor required for persistent murine renal infections.
Highlights
Bacterial pathogens often encounter acidic environments within host tissues and employ several direct and indirect defense measures [1]
The function of urease in S. aureus is not clear, recent evidence suggests that urease is important for acid resistance in various niches
Previous work has documented that aerobic growth of S. aureus in tryptic soy broth (TSB) containing excess glucose (35–45 mM) impairs stationary phase survival of S. aureus [7]
Summary
Bacterial pathogens often encounter acidic environments within host tissues and employ several direct and indirect defense measures [1]. Direct measures include the utilization of proton pumps and generation of alkaline compounds such as ammonia to neutralize pH Indirect methods such as damage repair, biofilm formation, and metabolic alterations, are utilized to rescue cell viability. It is important to note that S. aureus is sensitive to acetic acid stress when growing in the presence of excess glucose [7]. Weak acids such as acetic acid are unique in potentiating stationary phase cell death, in that unlike strong acids that fully dissociate in water, the undissociated weak acids can enter into the cytoplasm and reduce the intracellular pH by releasing protons. Based on global transcriptional studies, increased urease activity is thought to be a major contributor to acid resistance in S. aureus [10,11,12,13]
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