Multiple Targets of Nitric Oxide in the Tricarboxylic Acid Cycle of Salmonella enterica Serovar Typhimurium

Host nitric oxide (NO center dot) production is important for controlling intracellular bacterial pathogens, including Salmonella enterica serovar Typhimurium, but the underlying mechanisms are incompletely understood. S. Typhmurium 14028s is prototrophic for all amino acids but cannot synthesize methionine (M) or lysine (K) during nitrosative stress. Here, we show that NO center dot-induced MK auxotrophy results from reduced succinyl-CoA availability as a consequence of NO center dot targeting of lipoamide-dependent lipoamide dehydrogenase (LpdA) activity. LpdA is an essential component of the pyruvate and alpha-ketoglutarate dehydrogenase complexes. Additional effects of NO center dot on gene regulation prevent compensatory pathways of succinyl-CoA production. Microarray analysis indicates that over 50% of the transcriptional response of S. Typhimurium to nitrosative stress is attributable to LpdA inhibition. Bacterial methionine transport is essential for virulence in NO center dot-producing mice, demonstrating that NO center dot-induced MK auxotrophy occurs in vivo. These observations underscore the importance of metabolic targets for antimicrobial actions of NO center dot.