S-nitrosated α-1-acid glycoprotein kills drug-resistant bacteria and aids survival in sepsis

Kaori Watanabe, Yu Ishima, Takaaki Akaike, Tomohiro Sawa, Teruo Kuroda, Wakano Ogawa, Hiroshi Watanabe, Ayaka Suenaga, Toshiya Kai, Masaki Otagiri, Toru Maruyama

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9 Citations (Scopus)

Abstract

Treating infections with exogenous NO, which shows broad-spectrum antimicrobial activity, appears to be effective. Similar to NO biosynthesis, biosynthesis of α-1-acid glycoprotein variant A (AGPa), with a reduced cysteine (Cys149), increases markedly during inflammation and infection. We hypothesized that AGPa is an S-nitrosation target in acute-phase proteins. This study aimed to determine whether S-nitrosated AGPa (SNO-AGPa) may be the first compound of this novel antibacterial class against multidrug-resistant bacteria. AGPa was incubated with RAW264.7 cells activated by lipopolysaccharide and interferon-γ. The antimicrobial effects of SNO-AGPa were determined by measuring the turbidity of the bacterial suspensions in vitro and survival in a murine sepsis model in vivo, respectively. Results indicated that endogenous NO generated by activated RAW264.7 cells caused S-nitrosation of AGPa at Cys149. SNO-AGPa strongly inhibited growth of gram-positive, gram-negative, and multidrug-resistant bacteria and was an extremely potent bacteriostatic compound (IC50: 10-9 to 10-6 M). The antibacterial mechanism of SNO-AGPa involves S-transnitrosation from SNO-AGPa to bacterial cells. Treatment with SNO-AGPa, but not with AGPa, markedly reduced bacterial counts in blood and liver in a mouse sepsis model. The sialyl residues of AGPa seem to suppress the antibacterial activity, since SNO-asialo AGPa was more potent than SNO-AGPa.

Original languageEnglish
Pages (from-to)391-398
Number of pages8
JournalFASEB Journal
Volume27
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

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Keywords

  • Acute-phase protein
  • Nitric oxide
  • Post-translational modification

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Watanabe, K., Ishima, Y., Akaike, T., Sawa, T., Kuroda, T., Ogawa, W., Watanabe, H., Suenaga, A., Kai, T., Otagiri, M., & Maruyama, T. (2013). S-nitrosated α-1-acid glycoprotein kills drug-resistant bacteria and aids survival in sepsis. FASEB Journal, 27(1), 391-398. https://doi.org/10.1096/fj.12-217794