Urease Activity Represents an Alternative Pathway for Mycobacterium tuberculosis Nitrogen Metabolism

Abstract

dUrease represents a critical virulence factor for some bacterial species through its alkalizing effect, which helps neutralize the acidic microenvironment of the pathogen. In addition, urease serves as a nitrogen source provider for bacterial growth. Pathogenic mycobacteria express a functional urease, but its role during infection has yet to be characterized. In this study, we constructed a urease-deficient Mycobacterium tuberculosis strain and confirmed the alkalizing effect of the urease activity within the mycobacterium-containing vacuole in resting macrophages but not in the more acidic phagolysosomal compartment of activated macrophages. However, the urease-mediated alkalizing effect did not confer any growth advantage on M. tuberculosis in macrophages, as evidenced by comparable growth profiles for the mutant, wild-type (WT), and complemented strains. In contrast, the urease-deficient mutant exhibited impaired in vitro growth compared to the WT and complemented strains when urea was the sole source of nitrogen. Substantial amounts of ammonia were produced by the WT and complemented strains, but not with the urease-deficient mutant, which represents the actual nitrogen source for mycobacterial growth. However, the ureasedeficient mutant displayed parental colonization profiles in the lungs, spleen, and liver in mice. Together, our data demonstrate a role for the urease activity in M. tuberculosis nitrogen metabolism that could be crucial for the pathogen's survival in nutrientlimited microenvironments where urea is the sole nitrogen source. Our work supports the notion that M. tuberculosis virulence correlates with its unique metabolic versatility and ability to utilize virtually any carbon and nitrogen sources available in its environment.

Improving the strength of sandy soils via ureolytic CaCO<sub>3</sub> solidification by <i>Sporosarcina ureae</i>

“…This was not observed for S. ureae, much like S. pasteurii. Urea is a nitrogen source for bacterial growth, often catabolized by urease (Lin et al, 2012), which has been found to be controlled by nitrogen levels and pH as well as other factors which can differ between bacterial species (Mobley et al, 1995(Mobley et al, , 2001). Our observations indicate that S. ureae selects for urea in a metabolic pattern potentially similar to S. pasteurii and quite differently from the Bacillus strains investigated here, which appear to have medium-dependent metabolism of urea.…”

Nickel and Human Health

“…On the other hand, the observation that M. tuberculosis urease expression and activity increase upon nitrogen deprivation [ 160 ], suggests that urea may be a potential source of nitrogen for M. tuberculosis . Consistently, this bacterium assimilates urea, as major nitrogen source, in an urease-dependent manner, this process generating ammonia, which is one of the key precursors for the biosynthesis of essential amino acids such as glutamate [ 159 ].…”

“…However, a recent study indicated that urease activity does not infl uence the general bacterial fi tness in vitro . In addition, the alkalizing effect of the M. tuberculosis urease activity has only been found in resting macrophages, while it is not present in the more acidic microenvironment of the phagolysosomal compartment of activated macrophages, suggesting that the alkalizing effect provided by the mycobacterial urease activity is somehow modest [ 159 ]. On the other hand, the observation that M. tuberculosis urease expression and activity increase upon nitrogen deprivation [ 160 ], suggests that urea may be a potential source of nitrogen for M. tuberculosis .…”

“…The apparent dispensability of urease activity in a mouse model suggests that other readily available nitrogen sources within the host cell could bypass the need for M. tuberculosis to metabolize urea, with a general functional redundancy, metabolic versatility, and compensatory mechanisms that characterize M. tuberculosis ability to adapt to virtually any microenvironment encountered in its host, in which carbon and nitrogen sources may vary qualitatively and quantitatively [ 159 ]. In addition, the ability of M. tuberculosis to infect extra-pulmonary sites may require the urease activity for bacillus persistence or replication at specifi c sites of infection within the host.…”

Improving the Strength of Sandy Soils via Ureolytic CaCO<sub>3</sub> Solidification by <i>Sporosarcina ureae</i>

“…This was not observed for S. ureae (p > 0.05) much like S. pasteurii. Urea is a nitrogen source for 530 bacterial growth, often catabolised by urease, (Lin et al, 2012) which has been found to be controlled by nitrogen levels and pH as well as other factors which can differ between bacterial species (Mobley et al, 1995; see also Mobley et al, 2001). Our observations indicate that S. ureae selects for urea in a metabolic pattern potentially similar to S. pasteurii and quite differently from the Bacillus strains investigated here, which appear to have medium-dependent metabolism of urea.…”