S-Nitrosated Alpha-1-acid Glycoprotein Kills Drug-resistant Bacteria and Aids Survival in Sepsis

• Project/Area Number: 24659076
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: MARUYAMA Toru 熊本大学, 薬学部, 教授 (90423657)
• Co-Investigator(Kenkyū-buntansha): 小田切 優樹 崇城大学, 薬学部, 教授 (80120145) ; 異島 優 熊本大学, 薬学部, 助教 (00457590)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: alpha-1酸性糖タンパク質 / 一酸化窒素 / 多剤耐性 / 抗菌活性 / α１－酸性糖タンパク質

Research Abstract

Treating infections with exogenous NO, with broad-spectrum antimicrobial activity, seems to be effective. Similar to NO biosynthesis, biosynthesis of alpha-1-acid glycoprotein variant A (AGPa), with a reduced cysteine, increases markedly during inflammation and infection. The purpose of this study was 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 activated RAW264.7 cells. 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. Treatment with SNO-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.

Research Products

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• [Journal Article] Cys34-cysteinylated human serum albumin is a sensitive plasma marker in oxidative stress-related chronic diseases (2014)
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• [Journal Article] Albumin Fusion Prolongs the Antioxidant and Anti-Inflammatory Activities of Thioredoxin in Mice with Acetaminophen-Induced Hepatitis (2014)
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• [Journal Article] Poly-s-nitrosated albumin as a safe and effective multifunctional antitumor agent : characterization, biochemistry and possible future therapeutic applications (2013)
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• [Journal Article] S-nitrosylated a-l-acid glycoprotein kills drug-resistant bacteria and aids survival in sepsis (2013)
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• [Journal Article] Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression. (2013)
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• [Journal Article] UW solution improved with high anti-apoptotic activity by S-nitrosated human serum albumin. (2013)
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• [Journal Article] Albumin domain II mutant with high bilirubin binding affinity has a great potential as serum bilirubin excretion enhancer for hyperbilirubinemia treatment. (2013)
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• [Journal Article] p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress byactivation of NADPH oxidase. (2013)
  • Author(s): Hiroshi Watanabe^*, Yohei Miyamoto^*,Daisuke Honda, Hisae Tariaka, Qiong Wu,Masayuki Endo, Tsuyoshi Noguchi, DaisukeKadowaki, Yu Ishima, Shunsuke Kotani,Makoto Nakajima, Keiichiro Kataoka,Shokei Kim-Mitsuyama, Motoko Tanaka,Masafumi Fukagawa, Masaki Otagiri, ToruMaruyama. (^*:Hiroshi Watanabe and YoheiMiyamoto contributed equally to this work.)
  • Journal Title: Kidney International Volume: (印刷中) Issue: 4 Pages: 582-592
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• [Journal Article] A human serum albumin-thioredoxin fusion protein prevents experimental contrast-induced nephropathy. (2013)
  • Author(s): Kodama A
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• [Journal Article] Interaction between two sulfate-conjugated uremic toxins, p-cresyl sulfate and indoxyl sulfate, during binding with human serum albumin. (2013)
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  • Journal Title: Biochim Biophys Acta. Volume: 40 Issue: 7 Pages: 1423-8
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• [Journal Article] S-Guanylation of human serum albumin is a unique posttranslational modification and results in a novel class of antibacterial agents (2012)
  • Author(s): Ishima Y, Hoshino H, Shinagawa T, Watanabe K, Akaike T, Sawa T, Kragh-Hansen U, Kai T, Watanabe H, Maruyama T, and Otagiri M
  • Journal Title: J. Pharm. Sci Volume: 101 Issue: 9 Pages: 3222-3229
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• [Journal Article] α1-acid glycoprotein up-regulates CD163 via TLR4/CD14 pathway: possible protection against hemolysis-induced oxidative stress. (2012)
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• [Journal Article] Elucidation of the therapeutic enhancer mechanism of poly-S-nitrosated human serum albumin against multidrug-resistant tumor in animal models. (2012)
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• [Journal Article] A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal tubular cells via the generation of a radical intermediate. (2012)
  • Author(s): Yohei Miyamoto, Yasunori Katsumi Mera, Hiroshi Watanabe, Daisuke Kadowaki, Yu Ishima, Victor Tuan Giam Chuang, Keizo Sato, Masaki Otagiri, Toru Maruyama.
  • Journal Title: Biochemical Pharmacology Volume: 84 Issue: 9 Pages: 1207-1214
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  • Peer Reviewed
• [Journal Article] Characterization of the hepatic cellular uptake of α_1-acid glycoprotein (AGP), Part 1 : A peptide moiety of human AGP is recognized by the hemoglobin β-chain on mouse liver parenchymal cells (2011)
  • Author(s): 西弘二、小森久和
  • Journal Title: Journal of Pharmaceutical Sciences Volume: 101 Issue: 4 Pages: 1599-1606
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  • Peer Reviewed
• [Journal Article] Characterization of the hepatic cellular uptake of α_1-acid glycoprotein (AGP), Part 2 : Involvement of the hemoglobin β-chain on plasma membranes in the uptake of human AGP by liver parenchymal cells (2011)
  • Author(s): 小森久和
  • Journal Title: Journal of Pharmaceutical Sciences Volume: 101 Issue: 4 Pages: 1607-1615
  • DOI: 10.1002/jps.22804
  • Peer Reviewed
• [Presentation] 多剤耐性菌に対するS-ニトロソ化α1酸性糖タンパク質の抗菌作用渡邊佳織 (2014)
  • Author(s): 異島優、黒田照夫、小川和加野、渡邊博志、甲斐俊哉、小田切優樹、丸山徹
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本 : くまもと森都心プラザ
• [Presentation] 多剤耐性菌に対するS-ニトロソ化α1酸性糖タンパク質の抗菌作用 (2014)
  • Author(s): 渡邊佳織
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本大学（熊本県熊本市）
• [Presentation] Alpha1-酸性糖タンパク質バリアント間のリガンド結合選択性機序解明 (2013)
  • Author(s): 石井宏志、中村照也、小野知実、和泉実代子、渡邊博志、小田切優樹、山縣ゆり子、丸山徹
  • Organizer: 第30回日本薬学会九州支部大会
  • Place of Presentation: 長崎国際大学
• [Presentation] S-nitrosated a-1-acid glycoprotein kills drug-resistant bacteria and aids survival in sepsis (2013)
  • Author(s): Kaori Watanabe, Yu Ishima, Teruo Kuroda, Wakano Ogawa, Hiroshi Watanabe, Ayaka Suenaga, Toshiya Kai, Masaki Otagiri, and Toru Maruyama
  • Organizer: Asian Federation for Pharmaceutical Sciences 2013
  • Place of Presentation: Ramada Plaza Jeju Hotel, Jeju, Korea
• [Presentation] A human serum albumin–thioredoxin fusion protein prevents experimental contrast-induced nephropathy (2013)
  • Author(s): Hiroshi Watanabe, Azusa Kodama, Ryota Tanaka, Hisae Tanaka, Victor Tuan Giam Chuang, Yu Ishima, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama
  • Organizer: Asian Federation for Pharmaceutical Sciences 2013
  • Place of Presentation: Ramada Plaza Jeju Hotel, Jeju, Korea
• [Presentation] S-NITROSATEDα-1-ACID GLYCOPROTEIN KILLS DRUG-RESISTANT BACTERIA AND AIDS SURVIVAL IN SEPSIS (2013)
  • Author(s): Kaori Watanabe, Yu Ishima, Teruo Kuroda, Wakano Ogawa, Hiroshi Watanabe, Ayaka Suenaga, Toshiya Kai, Masaki Otagiri, Toru Maruyama
  • Organizer: 日本薬物動態学会第28回年会
  • Place of Presentation: 東京 : タワーホール船堀
• [Presentation] Poly-S-nitrosated Human Serum Albumin inhibits the Expression of P-glycoprotein Transporter in Human Multidrug-resistant Tumor (2013)
  • Author(s): Yu Ishima, Marie Hara, Hiroshi Watanabe, Masaki Otagiri, Toru Maruyama
  • Organizer: The 5th Asian Arden conference
  • Place of Presentation: Aichi Gakuin University
• [Presentation] Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression (2013)
  • Author(s): Ryota Tanaka, Hiroshi Watanabe, Yu Ishima, Masaki Otagiri, Toru Maruyama
  • Organizer: The 5th Asian Arden conference
  • Place of Presentation: Aichi Gakuin University
• [Presentation] 高分子抗癌剤の腫瘍集積性を高めるS-ニトロソ化アルブミンダイマーのEPR効果増強作用 (2013)
  • Author(s): 異島優、方軍、前田浩、渡邊博志、小田切優樹、丸山徹
  • Organizer: 第13回日本NO学会学術集会
  • Place of Presentation: 沖縄県医師会館
• [Presentation] 尿毒症物質インドキシル硫酸の生物活性に及ぼす活性酸化窒素種の影響成底徹 (2013)
  • Author(s): 異島優、小谷俊介、中島誠、渡邊博志、小田切優樹、丸山徹
  • Organizer: 第13回日本NO学会学術集会
  • Place of Presentation: 沖縄県医師会館
• [Presentation] クッパー細胞選択的チオール送達によるアセトアミノフェン肝障害治療法の開発 (2013)
  • Author(s): 前田仁志、平田憲史郎、渡邊博志、異島優、末永綾香、小田切優樹、丸山徹
  • Organizer: 日本薬剤学会第28年会
  • Place of Presentation: 愛知、ウインクあいち
• [Presentation] アルブミン-チオレドキシン融合体によるシスプラチン腎症予防効果 (2013)
  • Author(s): 小玉あずさ、田中遼大、渡邊博志、異島優、深川雅史、小田切優樹、丸山徹
  • Organizer: 日本薬剤学会第28年会
  • Place of Presentation: 愛知、ウインクあいち
• [Presentation] 高分子抗癌剤の腫瘍集積性を高めるS-ニトロソ化アルブミンダイマーのEPR効果増強作用 (2013)
  • Author(s): 異島優、方軍、前田浩、渡邊博志、小田切優樹、丸山徹
  • Organizer: 日本薬剤学会第28年会
  • Place of Presentation: 愛知、ウインクあいち
• [Presentation] アルブミン-チオレドキシン融合蛋白質はヨード造影剤腎症の発症を予防する (2013)
  • Author(s): 渡邊博志
  • Organizer: 第56回 日本腎臓学会学術総会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] 高分子抗癌剤の腫瘍集積性を高めるS-ニトロソ化アルブミンダイマーのEPR効果増強作用 (2013)
  • Author(s): 異島 優
  • Organizer: 日本薬剤学会第28年会
  • Place of Presentation: ウインクあいち（愛知県名古屋市中村区）
• [Presentation] S-ニトロソ化により獲得するα1-酸性糖タンパク質（AGP）の抗菌活性 (2013)
  • Author(s): 異島 優
  • Organizer: 第24回日本生体防御学会学術集会
  • Place of Presentation: くまもと森都心プラザ（熊本県熊本市）
• [Presentation] S-NITROSATED α-1-ACID GLYCOPROTEIN KILLS DRUG-RESISTANT BACTERIA AND AIDS SURVIVAL IN SEPSIS (2013)
  • Author(s): Kaori Watanabe
  • Organizer: 日本薬物動態学会 第28回年会
  • Place of Presentation: タワーホール船堀（東京都江戸川区）
• [Presentation] S-ニトロソ化に伴うα1-酸性糖タンパク質の抗菌機能獲得と感染症治療への応用 (2012)
  • Author(s): 渡辺佳織、異島優、黒田照夫、小川和加野、渡邊博志、小田切優樹、丸山徹
  • Organizer: 日本動物実験代替法学会第25回
  • Place of Presentation: 慶應義塾大学薬学部芝共立キャンパス
• [Presentation] S-ニトロソ化に伴うα1-酸性糖タンパク質(AGP)の抗菌機能獲得と感染症治療への応用 (2012)
  • Author(s): 渡辺佳織、異島優、赤池孝章、澤智裕、黒田照夫、小川和加野、渡邊博志、甲斐俊哉、小田切優樹、丸山徹
  • Organizer: 第34回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 京都大学薬学部
• [Presentation] S-ニトロソ化に伴うα1-酸性糖タンパク質(AGP)の抗菌機能獲得と感染症治療への応用 (2012)
  • Author(s): 渡辺佳織、異島優、赤池孝章、澤智裕、黒田照夫、小川和加野、渡邊博志、甲斐俊哉、小田切優樹、丸山徹
  • Organizer: 第12回日本NO学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] S-ニトロソ化アルブミンにより抗アポトーシス効果を付与した改良型臓器保存液の開発 (2012)
  • Author(s): 異島優、品川拓也、米重梓二、甲斐俊哉、赤池孝章、小田切優樹、丸山徹
  • Organizer: 第12回日本NO学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] S-ニトロソ化アルブミンダイマーはEPR効果を増強する (2012)
  • Author(s): 井上亜希、異島優、方軍、前田浩、小田切優樹、渡邊博志、丸山徹
  • Organizer: 日本薬剤学会第27年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] S -ニトロソ化アルブミンダイマーはEPR効果を増強する (2012)
  • Author(s): 井上 亜希
  • Organizer: 日本薬剤学会第２７年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] ブレオマイシン誘発肺線維症に対するアルブミン-チオレドキシン融合体の有用性評価 (2012)
  • Author(s): 田中 遼大
  • Organizer: 日本薬剤学会第２７年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] 新規翻訳後修飾体であるS -グアニル化アルブミンは抗菌効果を発揮する (2012)
  • Author(s): 異島 優
  • Organizer: 日本薬剤学会第２７年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] 骨髄指向性を有する新規エリスロポエチン製剤の開発 (2012)
  • Author(s): 宮崎 裕理
  • Organizer: 日本薬剤学会第２７年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] アルギニンペプチドを利用した細胞膜透過型アルブミンの設計と評価 (2012)
  • Author(s): 濱崎 慶輔
  • Organizer: 日本薬剤学会第２７年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] ファージディスプレイ法を用いた尿毒症物質3-carboxy-4-methyl-5-propyl-2-furan（CMPF）高親和性アルブミン変異体の設計 (2012)
  • Author(s): 西村 知晃
  • Organizer: 日本薬剤学会第２７年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] In vivoファージディスプレイ法を用いた新規腎送達ペプチドの探索 (2012)
  • Author(s): 弥永 直樹
  • Organizer: 日本薬剤学会第２７年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress through the activation of NADPH oxidase (2012)
  • Author(s): Hiroshi Watanabe
  • Organizer: 49th ERA-EDTA Congress
  • Place of Presentation: Paris, France
• [Presentation] A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate accumulates in proximal tubular cells and induces cell damage through increasing oxidative stress (2012)
  • Author(s): Yohei Miyamoto
  • Organizer: 49th ERA-EDTA Congress
  • Place of Presentation: Paris, France
• [Presentation] S-ニトロソ化に伴うα1-酸性糖タンパク質（AGP）の抗菌機能獲得と感染症治療への応用 (2012)
  • Author(s): 渡辺佳織
  • Organizer: 第12回日本NO学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] ヒト血清アルブミンドメインIIによるビリルビン尿中排泄促進作用 (2012)
  • Author(s): 小田切 優樹
  • Organizer: 第28回日本DDS学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
• [Presentation] 高分子抗癌剤の腫瘍集積性を高めるS - ニトロソ化アルブミンダイマーのEPR 効果増強作用 (2012)
  • Author(s): 異島 優
  • Organizer: 第28回日本DDS学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
• [Remarks]
  • URL: http://www.pharm.kumamoto-u.ac.jp/Labs/Yakuzai/
• [Remarks] 熊本大学薬学部薬剤学分野
  • URL: http://www.pharm.kumamoto-u.ac.jp/Labs/Yakuzai/
• [Patent(Industrial Property Rights)] 腎臓集積性を示すペプチド、薬物担体、製剤、医 薬組成物 (2012)
  • Inventor(s): 渡邊博志
  • Industrial Property Rights Holder: ニプロ株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-097763
  • Filing Date: 2012-04-23
• [Patent(Industrial Property Rights)] 細胞膜透過性を有する製剤、細胞膜透過性組成 物及び薬物輸送方法 (2012)
  • Inventor(s): 渡邊博志
  • Industrial Property Rights Holder: ニプロ株式会社
  • Industrial Property Rights Type: 特許
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  • Filing Date: 2012-04-23