Entereopathogenic Salmonella cause debilitating diseases in millions of people every year worldwide. As antibiotic treatments for Salmonella fail due to increased prevalence of antimicrobial resistance, generation of novel anti-Salmonella therapeutics becomes more pressing and will be aided by extensive knowledge of these bacteria. To that extent, we have discovered novel mechanisms by which Salmonella uses its nucleotide metabolism to empower its virulence. In Salmonella, the signaling nucleotides guanosine tetraphosphate and pentaphosphate [(p)ppGpp], synthesized by RelA and SpoT, regulate stress responses and virulence programs; however, the specific roles for these synthetases in Salmonella pathogenesis have not been defined. Herein, we document that Salmonella treated with nitric oxide (NO) produce (p)ppGpp from RelA, in a process that is activated by the functional amino acid auxotrophies associated with nitrosative stress. RelA-synthesized (p)ppGpp regulates amino acid biosynthetic gene expression, thereby facilitating expression of the antinitrosative defense Hmp. RelA is not the only important (p)ppGpp-synthetase in Salmonella pathogenesis. SpoT, activated by the environment of the phagosomal lumen, synthesizes (p)ppGpp to potentiate expression of the type-III secretion system encoded within the Salmonella pathogenicity island 2. Salmonella unable to produce (p)ppGpp from RelA or SpoT are attenuated. These studies reveal a model where unique roles of (p)ppGpp synthesized by either RelA or SpoT support Salmonella pathogenesis. In addition to synthesizing (p)ppGpp, SpoT also hydrolyzes these nucleotide alarmones. A Salmonella strain deficient in SpoT-mediated hydrolysis overproduces (p)ppGpp and is severely attenuated, indicating that (p)ppGpp hydrolysis is as important as its synthesis in Salmonella pathogenesis. In addition to stimulating (p)ppGpp synthesis, NO triggers remodeling of triphosphate nucleotides (NTP) metabolism, the extent of which depends on the carbon source and the underlying metabolic pathways supporting ATP synthesis. For instance, glycolytic Salmonella retain higher NTP pools after NO treatment than counterparts undergoing oxidative phosphorylation. Accordingly, zinc-dependent glycolysis, but not oxidative phosphorylation, enable Salmonella to resist to nitrosative stress in murine models of infection. Cumulatively, my research has identified unique roles for RelA and SpoT in the pathogenesis of Salmonella and demonstrates that Salmonella reprograms nucleotide metabolism and uses zinc-enabled glycolysis to mitigate the depletion of ATP triggered by nitrosative stress.