Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jul 3;92(14):6399–6403. doi: 10.1073/pnas.92.14.6399

Genetic and redox determinants of nitric oxide cytotoxicity in a Salmonella typhimurium model.

M A De Groote 1, D Granger 1, Y Xu 1, G Campbell 1, R Prince 1, F C Fang 1
PMCID: PMC41525  PMID: 7604003

Abstract

Paradoxically, nitric oxide (NO) has been found to exhibit cytotoxic, antiproliferative, or cytoprotective activity under different conditions. We have utilized Salmonella mutants deficient in antioxidant defenses or peptide transport to gain insights into NO actions. Comparison of three NO donor compounds reveals distinct and independent cellular responses associated with specific redox forms of NO. The peroxynitrite (OONO-) generator 3-morpholinosydnonimine hydrochloride mediates oxygen-dependent Salmonella killing, whereas S-nitrosoglutathione (GSNO) causes oxygen-independent cytostasis, and the NO. donor diethylenetriamine-nitric oxide adduct has no antibacterial activity. GSNO has the greatest activity for stationary cells, a characteristic relevant to latent or intracellular pathogens. Moreover, the cytostatic activity of GSNO may best correlate with antiproliferative or antimicrobial effects of NO, which are unassociated with overt cell injury. dpp mutants defective in active dipeptide transport are resistant to GSNO, implicating heterolytic NO+ transfer rather than homolytic NO. release in the mechanism of cytostasis. This transport system may provide a specific pathway for GSNO-mediated signaling in biological systems. The redox state and associated carrier molecules are critical determinants of NO activity.

Full text

PDF
6399

Images in this article

6400Fig. 1
on p.6400
6401Fig. 2
on p.6401
6401Fig. 3
on p.6401
6401Fig. 4
on p.6401
6402Fig. 5
on p.6402
6402Fig. 6
on p.6402

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abouhamad W. N., Manson M., Gibson M. M., Higgins C. F. Peptide transport and chemotaxis in Escherichia coli and Salmonella typhimurium: characterization of the dipeptide permease (Dpp) and the dipeptide-binding protein. Mol Microbiol. 1991 May;5(5):1035–1047. doi: 10.1111/j.1365-2958.1991.tb01876.x. [DOI] [PubMed] [Google Scholar]
  2. Arroyo P. L., Hatch-Pigott V., Mower H. F., Cooney R. V. Mutagenicity of nitric oxide and its inhibition by antioxidants. Mutat Res. 1992 Mar;281(3):193–202. doi: 10.1016/0165-7992(92)90008-6. [DOI] [PubMed] [Google Scholar]
  3. Bauer A. W., Kirby W. M., Sherris J. C., Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol. 1966 Apr;45(4):493–496. [PubMed] [Google Scholar]
  4. Beauchamp C., Fridovich I. Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem. 1971 Nov;44(1):276–287. doi: 10.1016/0003-2697(71)90370-8. [DOI] [PubMed] [Google Scholar]
  5. Brunelli L., Crow J. P., Beckman J. S. The comparative toxicity of nitric oxide and peroxynitrite to Escherichia coli. Arch Biochem Biophys. 1995 Jan 10;316(1):327–334. doi: 10.1006/abbi.1995.1044. [DOI] [PubMed] [Google Scholar]
  6. Buchmeier N. A., Libby S. J., Xu Y., Loewen P. C., Switala J., Guiney D. G., Fang F. C. DNA repair is more important than catalase for Salmonella virulence in mice. J Clin Invest. 1995 Mar;95(3):1047–1053. doi: 10.1172/JCI117750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Buchmeier N. A., Lipps C. J., So M. Y., Heffron F. Recombination-deficient mutants of Salmonella typhimurium are avirulent and sensitive to the oxidative burst of macrophages. Mol Microbiol. 1993 Mar;7(6):933–936. doi: 10.1111/j.1365-2958.1993.tb01184.x. [DOI] [PubMed] [Google Scholar]
  8. Carlioz A., Touati D. Isolation of superoxide dismutase mutants in Escherichia coli: is superoxide dismutase necessary for aerobic life? EMBO J. 1986 Mar;5(3):623–630. doi: 10.1002/j.1460-2075.1986.tb04256.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Choi D. W. Nitric oxide: foe or friend to the injured brain? Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9741–9743. doi: 10.1073/pnas.90.21.9741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fang F. C., Libby S. J., Buchmeier N. A., Loewen P. C., Switala J., Harwood J., Guiney D. G. The alternative sigma factor katF (rpoS) regulates Salmonella virulence. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11978–11982. doi: 10.1073/pnas.89.24.11978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fierer J., Eckmann L., Fang F., Pfeifer C., Finlay B. B., Guiney D. Expression of the Salmonella virulence plasmid gene spvB in cultured macrophages and nonphagocytic cells. Infect Immun. 1993 Dec;61(12):5231–5236. doi: 10.1128/iai.61.12.5231-5236.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gaston B., Reilly J., Drazen J. M., Fackler J., Ramdev P., Arnelle D., Mullins M. E., Sugarbaker D. J., Chee C., Singel D. J. Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10957–10961. doi: 10.1073/pnas.90.23.10957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Green L. C., Wagner D. A., Glogowski J., Skipper P. L., Wishnok J. S., Tannenbaum S. R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982 Oct;126(1):131–138. doi: 10.1016/0003-2697(82)90118-x. [DOI] [PubMed] [Google Scholar]
  14. Haddad I. Y., Pataki G., Hu P., Galliani C., Beckman J. S., Matalon S. Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. J Clin Invest. 1994 Dec;94(6):2407–2413. doi: 10.1172/JCI117607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hausladen A., Fridovich I. Superoxide and peroxynitrite inactivate aconitases, but nitric oxide does not. J Biol Chem. 1994 Nov 25;269(47):29405–29408. [PubMed] [Google Scholar]
  16. Hibbs J. B., Jr, Taintor R. R., Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987 Jan 23;235(4787):473–476. doi: 10.1126/science.2432665. [DOI] [PubMed] [Google Scholar]
  17. Higgins C. F. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992;8:67–113. doi: 10.1146/annurev.cb.08.110192.000435. [DOI] [PubMed] [Google Scholar]
  18. Higgins C. F., Hiles I. D., Salmond G. P., Gill D. R., Downie J. A., Evans I. J., Holland I. B., Gray L., Buckel S. D., Bell A. W. A family of related ATP-binding subunits coupled to many distinct biological processes in bacteria. Nature. 1986 Oct 2;323(6087):448–450. doi: 10.1038/323448a0. [DOI] [PubMed] [Google Scholar]
  19. Hughes K. T., Roth J. R. Transitory cis complementation: a method for providing transposition functions to defective transposons. Genetics. 1988 May;119(1):9–12. doi: 10.1093/genetics/119.1.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Huie R. E., Padmaja S. The reaction of no with superoxide. Free Radic Res Commun. 1993;18(4):195–199. doi: 10.3109/10715769309145868. [DOI] [PubMed] [Google Scholar]
  21. Incze K., Farkas J., Mihályi V., Zukál E. Antibacterial effect of cysteine-nitrosothiol and possible percursors thereof. Appl Microbiol. 1974 Jan;27(1):202–205. doi: 10.1128/am.27.1.202-205.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lipton S. A., Choi Y. B., Pan Z. H., Lei S. Z., Chen H. S., Sucher N. J., Loscalzo J., Singel D. J., Stamler J. S. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature. 1993 Aug 12;364(6438):626–632. doi: 10.1038/364626a0. [DOI] [PubMed] [Google Scholar]
  23. Loewen P. C., Hengge-Aronis R. The role of the sigma factor sigma S (KatF) in bacterial global regulation. Annu Rev Microbiol. 1994;48:53–80. doi: 10.1146/annurev.mi.48.100194.000413. [DOI] [PubMed] [Google Scholar]
  24. Mannick J. B., Asano K., Izumi K., Kieff E., Stamler J. S. Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell. 1994 Dec 30;79(7):1137–1146. doi: 10.1016/0092-8674(94)90005-1. [DOI] [PubMed] [Google Scholar]
  25. Morris S. L., Hansen J. N. Inhibition of Bacillus cereus spore outgrowth by covalent modification of a sulfhydryl group by nitrosothiol and iodoacetate. J Bacteriol. 1981 Nov;148(2):465–471. doi: 10.1128/jb.148.2.465-471.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  27. Nunoshiba T., deRojas-Walker T., Wishnok J. S., Tannenbaum S. R., Demple B. Activation by nitric oxide of an oxidative-stress response that defends Escherichia coli against activated macrophages. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9993–9997. doi: 10.1073/pnas.90.21.9993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Prince R. W., Xu Y., Libby S. J., Fang F. C. Cloning and sequencing of the gene encoding the RpoS (KatF) sigma factor from Salmonella typhimurium 14028s. Biochim Biophys Acta. 1994 Sep 13;1219(1):198–200. doi: 10.1016/0167-4781(94)90271-2. [DOI] [PubMed] [Google Scholar]
  29. Radi R., Beckman J. S., Bush K. M., Freeman B. A. Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem. 1991 Mar 5;266(7):4244–4250. [PubMed] [Google Scholar]
  30. Rayssiguier C., Thaler D. S., Radman M. The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch-repair mutants. Nature. 1989 Nov 23;342(6248):396–401. doi: 10.1038/342396a0. [DOI] [PubMed] [Google Scholar]
  31. Reimer L. G., Stratton C. W., Reller L. B. Minimum inhibitory and bactericidal concentrations of 44 antimicrobial agents against three standard control strains in broth with and without human serum. Antimicrob Agents Chemother. 1981 Jun;19(6):1050–1055. doi: 10.1128/aac.19.6.1050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Stamler J. S. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell. 1994 Sep 23;78(6):931–936. doi: 10.1016/0092-8674(94)90269-0. [DOI] [PubMed] [Google Scholar]
  33. Stamler J. S., Simon D. I., Osborne J. A., Mullins M. E., Jaraki O., Michel T., Singel D. J., Loscalzo J. S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):444–448. doi: 10.1073/pnas.89.1.444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Suzuki H., Kumagai H., Tochikura T. Isolation, genetic mapping, and characterization of Escherichia coli K-12 mutants lacking gamma-glutamyltranspeptidase. J Bacteriol. 1987 Sep;169(9):3926–3931. doi: 10.1128/jb.169.9.3926-3931.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Volkert M. R., Hajec L. I., Matijasevic Z., Fang F. C., Prince R. Induction of the Escherichia coli aidB gene under oxygen-limiting conditions requires a functional rpoS (katF) gene. J Bacteriol. 1994 Dec;176(24):7638–7645. doi: 10.1128/jb.176.24.7638-7645.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wink D. A., Kasprzak K. S., Maragos C. M., Elespuru R. K., Misra M., Dunams T. M., Cebula T. A., Koch W. H., Andrews A. W., Allen J. S. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science. 1991 Nov 15;254(5034):1001–1003. doi: 10.1126/science.1948068. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES