NtrC Increases Fitness of Salmonella enterica Serovar Typhimurium under Low and Fluctuating Nutrient Conditions.

Enteric pathogens cycle between nutrient-rich host and nutrient-poor external environment. These pathogens compete for nutrients while cycling between host and external environment, and often experience starvation. In this context, we have studied the role of a global regulator (NtrC) of Salmonella Typhimurium. The C knockout mutation caused extended lag phase (8 h) and slow growth in the minimal medium. In lag phase, the wild-type cells showed ~60-fold more expression of C gene. Gene expression studies and biochemical assays showed that the extended lag phase and slow growth is due to slow metabolism, instead of nitrogen transport. Further, we observed that C knockout mutation led extended lag phase and slow growth, made ΔC mutant unable to compete with wild-type Typhimurium in both static and fluctuating nutrient condition. In addition to this, ΔC knockout mutant was unable to survive long-term nitrogen starvation (150 days). The nutrient recycling assays and gene expression studies revealed that rC gene is essential for rapid recycling of nutrients from the dead cells. Moreover, in the absence of C gene, magnesium limits the nutrient recycling efficiency of Typhimurium. Therefore, the C gene, which is often studied with respect to nitrogen scavenging in a low nitrogen growing condition, is required even in the adequate supply of nitrogen to maintain optimal growth and fast exit from the lag phase. Hence, we conclude that, the C expression is essential for competitive fitness of Typhimurium under the low and fluctuating nutrient condition. Typhimurium, both in host and external environment, faces enormous competition from other microorganisms. The competition may take place either in static or in fluctuating nutrient conditions. Thus, how Typhimurium survives under such overlapping stress conditions remained unclear. Therefore, using Typhimurium as model organism we report that a global regulator NtrC, found in enteric bacteria like Escherichia coli and Salmonella, activates the set of genes and operons involved in rapid adaptation and efficient nutrient recycling/scavenging. These properties enable cells to compete with other microbes under the characteristic feast-or-famine lifestyle of Typhimurium. Therefore, this work helps us to understand the starvation physiology of the enteric bacterial pathogen Typhimurium.