Multiple targets of nitric oxide in the tricarboxylic acid cycle of salmonella enterica serovar typhimurium

Anthony R. Richardson, Elizabeth C. Payne, Noah Younger, Joyce E. Karlinsey, Vinai C. Thomas, Lynne A. Becker, William W. Navarre, Margaret E. Castor, Stephen J. Libby, Ferric C. Fang

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Host nitric oxide (NO) 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-induced MK auxotrophy results from reduced succinyl-CoA availability as a consequence of NO targeting of lipoamide-dependent lipoamide dehydrogenase (LpdA) activity. LpdA is an essential component of the pyruvate and α-ketoglutarate dehydrogenase complexes. Additional effects of NO 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-producing mice, demonstrating that NO-induced MK auxotrophy occurs in vivo. These observations underscore the importance of metabolic targets for antimicrobial actions of NO.

Original languageEnglish (US)
Pages (from-to)33-43
Number of pages11
JournalCell Host and Microbe
Volume10
Issue number1
DOIs
StatePublished - Jul 21 2011

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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    Richardson, A. R., Payne, E. C., Younger, N., Karlinsey, J. E., Thomas, V. C., Becker, L. A., Navarre, W. W., Castor, M. E., Libby, S. J., & Fang, F. C. (2011). Multiple targets of nitric oxide in the tricarboxylic acid cycle of salmonella enterica serovar typhimurium. Cell Host and Microbe, 10(1), 33-43. https://doi.org/10.1016/j.chom.2011.06.004