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

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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
Issue number1
Publication statusPublished - 2013 Jan


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


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