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S ‐nitrosated α‐1‐acid glycoprotein kills drug‐resistant bacteria and aids survival in sepsis
Author(s) -
Watanabe Kaori,
Ishima Yu,
Akaike Takaaki,
Sawa Tomohiro,
Kuroda Teruo,
Ogawa Wakano,
Watanabe Hiroshi,
Suenaga Ayaka,
Kai Toshiya,
Otagiri Masaki,
Maruyama Toru
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-217794
Subject(s) - microbiology and biotechnology , antimicrobial , bacteria , nitrosation , lipopolysaccharide , sepsis , gram negative bacteria , antibiotics , in vivo , in vitro , chemistry , biology , pharmacology , immunology , biochemistry , escherichia coli , genetics , gene
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 (IC 50 : 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.—Watanabe, K., Ishima, Y., Akaike, T., Sawa, T., Kuroda, T., Ogawa, W., Watanabe, H., Suenaga, A., Kai, T., Otagiri, M., Maruyama, T. S ‐nitrosated α‐1‐acid glycoprotein kills drug‐resistant bacteria and aids survival in sepsis. FASEB J. 27, 391–398 (2013). www.fasebj.org