Molecular mechanisms for metabolisms of bacterial reactive sulfur species: implication in antibacterial resistance

• Project/Area Number: 15H03115
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biomolecular chemistry
• Research Institution: Kumamoto University
• Principal Investigator: Sawa Tomohiro 熊本大学, 大学院生命科学研究部(医), 教授 (30284756)
• Co-Investigator(Kenkyū-buntansha): 赤池 孝章 東北大学, 医学系研究科, 教授 (20231798) ; 居原 秀 大阪府立大学, 理学(系)研究科(研究院), 准教授 (60254447)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2016: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2015: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
• Keywords: 生体機能物質 / 活性イオウ分子 / 酸化ストレス / 抗生物質 / 薬剤耐性 / 活性イオウ / 細菌 / 活性酸素 / パースルフィド / グラム陰性菌

Outline of Final Research Achievements

Antixoxidative machineries that eliminate reactive oxygen species are of great benefit to bacteria to grow aerobically and to escape from oxygen-dependent bacterial killing by macrophages. Cysteine persulfide and glutathione persulfide are present abundantly in mammalian cells and act as potent antioxidants. Here we investigated the occurrence of persulfide in Gram-negative bacteria. Roles of persulfide species on bacterial resistance against oxidative stress was studied. Cysteine persulfide and glutathione persulfide/trisulfide were detected in all bacteria studied. Treatment of Salmonella Typhimurium with persulfide donors significantly increased intracellular persulfide levels. More importantly, persulfide boosted bacteria became highly resistant against oxidative stress-mediated bacterial killing induced by hydrogen peroxide challenging and by macrophages. These data suggest the importance of reactive persulfides in bacterial resistance against oxidative stress.

Research Products

• [Journal Article] A Simple PLGA-AgNPL Film for Antibiofilm Formation by Contact Bactericidal Activity (2018)
  • Author(s): Kyaw Kaung、Motoyama Nana、Ichimaru Hiroaki、Harada Ayaka、Morimura Shigeru、Ono Katsuhiko、Tsutsuki Hiroyasu、Sawa Tomohiro、Miyazawa Yuta、Mizoguchi Daigou、Niidome Takuro
  • Journal Title: Chemistry Letters Volume: 47 Issue: 3 Pages: 308-310
  • DOI: 10.1246/cl.171022
  • NAID: 130006434041
  • Peer Reviewed
• [Journal Article] Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons (2018)
  • Author(s): Masuda Kumiko、Tsutsuki Hiroyasu、Kasamatsu Shingo、Ida Tomoaki、Takata Tsuyoshi、Sugiura Kikuya、Nishida Motohiro、Watanabe Yasuo、Sawa Tomohiro、Akaike Takaaki、Ihara Hideshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 3 Pages: 2165-2170
  • DOI: 10.1016/j.bbrc.2017.12.088
  • Peer Reviewed / Open Access
• [Journal Article] Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics (2017)
  • Author(s): Akaike Takaaki、、、Nishida Motohiro（4）、、、、、、Fujii Shigemoto（20）、、、Motohashi Hozumi（26）
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 1177-1177
  • DOI: 10.1038/s41467-017-01311-y
  • NAID: 120007134656
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage (2017)
  • Author(s): Hoshino Marie、Kaneko Kotaro、Miyamoto Yoichi、Yoshimura Kentaro、Suzuki Dai、Akaike Takaaki、Sawa Tomohiro、Ida Tomoaki、Fujii Shigemoto、Ihara Hideshi、Tanaka Junichi、Tsukuura Risa、Chikazu Daichi、Mishima Kenji、Baba Kazuyoshi、Kamijo Ryutaro
  • Journal Title: Free Radic Biol Med Volume: 110 Pages: 63-71
  • DOI: 10.1016/j.freeradbiomed.2017.05.022
  • Peer Reviewed / Open Access
• [Journal Article] Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells (2017)
  • Author(s): Ihara Hideshi、Kasamatsu Shingo、Kitamura Atsushi、Nishimura Akira、Tsutsuki Hiroyasu、Ida Tomoaki、Ishizaki Kento、Toyama Takashi、Yoshida Eiko、Abdul Hamid Hisyam、Jung Minkyung、Matsunaga Tetsuro、Fujii Shigemoto、Sawa Tomohiro、Nishida Motohiro、Kumagai Yoshito、Akaike Takaaki
  • Journal Title: Chem. Res. Toxicol Volume: 30 Issue: 9 Pages: 1673-1684
  • DOI: 10.1021/acs.chemrestox.7b00120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion. (2017)
  • Author(s): Takahashi N, Wei FY, Watanabe S, Hirayama M, Ohuchi Y, Fujimura A, Kaitsuka T, Ishii I, Sawa T, Nakayama H, Akaike T, Tomizawa K.
  • Journal Title: Nucleic Acids Res. Volume: 45 Issue: 1 Pages: 435-445
  • DOI: 10.1093/nar/gkw745
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Quantitative determination of polysulfide in albumins, plasma proteins and biological fluid samples using a novel combined assays approach (2017)
  • Author(s): keda, M. Ishima, Y. Shibata, A. Chuang, V. T. G. Sawa, T. Ihara, H. Watanabe, H. Xian, M. Ouchi, Y. Shimizu, T. Ando, H. Ukawa, M. Ishida, T. Akaike, T. Otagiri, M. Maruyama, T.
  • Journal Title: Analytica Chimica Acta Volume: 969 Pages: 18-25
  • DOI: 10.1016/j.aca.2017.03.027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synthesis of L-cysteine derivatives containing stable sulfur isotopes and application of this synthesis to reactive sulfur metabolome (2017)
  • Author(s): Ono K, Jung M, Zhang T, Tsutsuki H, Sezaki H, Ihara H, Wei FY, Tomizawa K, Akaike T, Sawa T.
  • Journal Title: Free Radic Biol Med Volume: 106 Pages: 69-79
  • DOI: 10.1016/j.freeradbiomed.2017.02.023
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synthesis and Characterization of 8-Nitroguanosine 3′,5′-Cyclic Monophosphorothioate Rp-Isomer as a Potent Inhibitor of Protein Kinase G1α (2017)
  • Author(s): Ahmed KA, Zhang T, Ono K, Tsutsuki H, Ida T, Akashi S, Miyata K, Oike Y, Akaike T, Sawa T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 3 Pages: 365-374
  • DOI: 10.1248/bpb.b16-00880
  • NAID: 130005398514
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Metabolomic profiling of reactive persulfides and polysulfides in the aqueous and vitreous humors. (2017)
  • Author(s): Kunikata H, Ida T, Sato K, Aizawa N, Sawa T, Tawarayama H, Murayama N, Fujii S, Akaike T, Nakazawa T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 41984-41984
  • DOI: 10.1038/srep41984
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Silver nanoparticles as potential antibiofilm agents against human pathogenic bacteria (2017)
  • Author(s): Kyaw K, Harada A, Ichimaru H, Kawagoe T, Yahiro K, Morimura S, Ono K, Tsutsuki H, Sawa T, Niidome T.
  • Journal Title: Chem Lett Volume: 46 Issue: 4 Pages: 594-596
  • DOI: 10.1246/cl.161198
  • NAID: 130005549076
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Superoxide generation from nNOS splice variants and its potential involvement in redox signal regulation (2017)
  • Author(s): Ihara H, Kitamura A, Kasamatsu S, Ida T, Kakihana Y, Tsutsuki H, Sawa T, Watanabe Y, Akaike T.
  • Journal Title: Biochem J Volume: 474 Issue: 7 Pages: 1149-1162
  • DOI: 10.1042/bcj20160999
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Protein polysulfidation-dependent persulfide dioxygenase activity of ethylmalonic encephalopathy protein 1 (2016)
  • Author(s): Jung M, Kasamatsu S, Matsunaga T, Akashi S, Ono K, Nishimura A, Morita M, Abdul Hamid H, Fujii S, Kitamura H, Sawa T, Ida T, Motohashi H, Akaike T.
  • Journal Title: Biochem Biophys Res Commun Volume: 480 Issue: 2 Pages: 180-186
  • DOI: 10.1016/j.bbrc.2016.10.022
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Endogenous occurrence of protein S-guanylation in Escherichia coli: target identification and genetic regulation. (2016)
  • Author(s): Tsutsuki, H., Jung, M., Zhang, T., Ono, K., Ida, T., Kunieda, K., Ihara, H., Akaike, T. and Sawa, T.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 478 Issue: 1 Pages: 7-11
  • DOI: 10.1016/j.bbrc.2016.07.110
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Persistent activation of cGMP-dependent protein kinase by a nitrated cyclic nucleotide via site specific protein S-guanylation (2016)
  • Author(s): Akashi S, Ahmed KA, Sawa T, Ono K, Tsutsuki H, Burgoyne JR, Ida T, Horio E, Prysyazhna O, Oike Y, Rahaman MM, Eaton P, Fujii S, Akaike T.
  • Journal Title: Biochemistry Volume: 55 Issue: 5 Pages: 751-761
  • DOI: 10.1021/acs.biochem.5b00774
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 8-Nitro-cGMP Enhances SNARE Complex Formation through S-Guanylation of Cys90 in SNAP25 (2015)
  • Author(s): K. Kunieda, H. Tsutsuki, T. Ida, Y. Kishimoto, S. Kasamatsu, T. Sawa, N. Goshima, M. Itakura, M. Takahashi, T. Akaike, H. Ihara
  • Journal Title: ACS Chemical Neuroscience Volume: 6 Issue: 10 Pages: 1715-1725
  • DOI: 10.1021/acschemneuro.5b00196
  • Peer Reviewed / Open Access
• [Journal Article] 8-Mercapto-cyclic GMP mediates hydrogen sulfide-induced stomatal closure in Arabidopsis. (2015)
  • Author(s): Honda K, Yamada N, Yoshida R, Ihara H, Sawa T, Akaike T, Iwai S.
  • Journal Title: Plant Cell Physiol. Volume: 56 Issue: 8 Pages: 1481-1489
  • DOI: 10.1093/pcp/pcv069
  • Peer Reviewed / Open Access
• [Journal Article] Reactive sulfur species-mediated activation of the Keap1-Nrf2 pathway by 1,2-napthoquinone through sulfenic acids formation under oxidative stress. (2015)
  • Author(s): Shinkai Y, Abiko Y, Ida T, Miura T, Kakehashi H, Ishii I, Nishida M, Sawa T, Akaike T, Kumagai Y.
  • Journal Title: Chem Res Toxicol. Volume: 印刷中 Issue: 5 Pages: 838-847
  • DOI: 10.1021/tx500416y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 細菌の硫化水素・RSSの代謝シグナル制御． (2015)
  • Author(s): 津々木博康、小野勝彦、澤 智裕
  • Journal Title: 細胞工学 Volume: 34 Pages: 392-395
  • Peer Reviewed
• [Journal Article] H.cinaediと敗血症 (2015)
  • Author(s): 河村好章、富田純子、岡本竜哉、澤 智裕、赤池孝章.
  • Journal Title: 臨床と微生物 Volume: 42 Pages: 177-182
  • Peer Reviewed
• [Presentation] 活性イオウによる酸化ストレス制御の分子機構 (2016)
  • Author(s): 澤 智裕
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 東北大学川内キャンパス
  • Year and Date: 2016-09-25
• [Presentation] 活性イオウによる酸化ストレス制御の分子機構 (2016)
  • Author(s): 澤 智裕
  • Organizer: 第69回日本酸化ストレス学会学術集会
  • Place of Presentation: 仙台国際ホール
  • Year and Date: 2016-08-30
• [Presentation] 親電子性ヌクレオチドによる細胞内レドックス調節機構とその制御 (2016)
  • Author(s): 澤 智裕
  • Organizer: 第43回日本毒性学会学術年会
  • Place of Presentation: ウインクあいち
  • Year and Date: 2016-06-29
• [Presentation] 親電子性ヌクレオチドによるcGMP依存性プロテインキナーゼのシステイン残基修飾を介した制御機能 (2016)
  • Author(s): 澤 智裕
  • Organizer: 第16回日本蛋白質科学会年会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2016-06-07
• [Presentation] 細菌におけるシステインパースルフィド関連分子の生成動態 (2016)
  • Author(s): 澤 智裕, 張 田力, 小野勝彦, 津々木博康, 赤池孝章
  • Organizer: 第89回日本細菌学会総会
  • Place of Presentation: 大阪国際交流センター（大阪市）
  • Year and Date: 2016-03-23
• [Presentation] 腸管出血性大腸菌毒素 Subtilase cytotoxin によるインフラマソーム抑制機構の解析 (2016)
  • Author(s): 津々木博康, Thianli Zhang, 小野勝彦, 八尋錦之助, 野田広俊, 澤 智裕
  • Organizer: 第89回日本細菌学会総会
  • Place of Presentation: 大阪国際交流センター（大阪市）
  • Year and Date: 2016-03-23
• [Presentation] チオール化合物とβラクタム系抗生物質との反応による付加体形成：抗菌作用への影響と標的タンパク質の同定 (2016)
  • Author(s): 小野勝彦, 津々木博康, 赤池孝章, 澤 智裕
  • Organizer: 第89回日本細菌学会総会
  • Place of Presentation: 大阪国際交流センター（大阪市）
  • Year and Date: 2016-03-23
• [Presentation] 酸化ストレスを抑える新しい分子の発見：炎症性疾患治療への展開を目指して (2016)
  • Author(s): 澤 智裕
  • Organizer: 第9回アトピー・乾癬学術講演会
  • Place of Presentation: ホテル日航熊本（熊本市）
  • Year and Date: 2016-01-28
  • Invited
• [Presentation] 蛋白質S-グアニル化とレドックスシグナル伝達制御 (2015)
  • Author(s): 澤 智裕
  • Organizer: 第39回蛋白質と酵素の構造と機能に関する九州シンポジウム
  • Place of Presentation: 別府豊泉荘（大分県別府市）
  • Year and Date: 2015-09-10
  • Invited
• [Presentation] 大腸菌における蛋白質S-グアニル化の制御因子と標的タンパク質の同定 (2015)
  • Author(s): 津々木博康、小野勝彦、井田智章、張 田力、居原 秀、赤池孝章、澤 智裕
  • Organizer: 第68回日本細菌学会九州支部総会第52回日本ウイルス学会九州支部総会
  • Place of Presentation: 別府コンベンションプラザ・ビーコンプラザ（大分県別府市）
  • Year and Date: 2015-09-04
• [Presentation] ヒト内在性レトロウイルスの転写因子の同定 (2015)
  • Author(s): 門出和精、寺沢広美、澤智裕、前田洋助
  • Organizer: 第68回日本細菌学会九州支部総会第52回日本ウイルス学会九州支部総会
  • Place of Presentation: 別府コンベンションプラザ・ビーコンプラザ（大分県別府市）
  • Year and Date: 2015-09-04
• [Presentation] 細菌におけるシステインパースルフィドおよび関連分子の生成動態 (2015)
  • Author(s): 小野勝彦、津々木博康、張 田力、赤池孝章、澤 智裕
  • Organizer: 第68回日本細菌学会九州支部総会第52回日本ウイルス学会九州支部総会
  • Place of Presentation: 別府コンベンションプラザ・ビーコンプラザ（大分県別府市）
  • Year and Date: 2015-09-04
• [Presentation] 蛋白質S-グアニル化と活性酸素シグナル伝達 (2015)
  • Author(s): 澤 智裕
  • Organizer: 日本プロテオーム学会2015年会 JHUPO第13回大会
  • Place of Presentation: くまもと森都心プラザ（熊本市）
  • Year and Date: 2015-07-23
• [Presentation] ポリエチレングリコール結合マンガンプロトフィリンの合成とその抗酸化活性の解析 (2015)
  • Author(s): 小野勝彦、方 軍、澤 智裕
  • Organizer: 第15回日本NO学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
  • Year and Date: 2015-06-26
• [Presentation] 大腸菌における蛋白質S－グアニル化：制御因子と標的タンパク質の同定 (2015)
  • Author(s): 津々木博康、小野勝彦、井田智章、藤井重元、松永哲郎、居原 秀、赤池孝章、澤 智裕
  • Organizer: 第15回日本NO学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
  • Year and Date: 2015-06-26
• [Presentation] 活性イオウ分子による抗酸化システム制御 (2015)
  • Author(s): 澤 智裕
  • Organizer: 第15回日本NO学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
  • Year and Date: 2015-06-26
  • Invited
• [Remarks] 熊本大学 微生物学分野
  • URL: http://kumadai-bisei.com
• [Patent(Industrial Property Rights)] イオウ原子を同位体標識したシステイン及びシステイン誘導体の合成法の確率 (2016)
  • Inventor(s): 澤 智裕、小野勝彦
  • Industrial Property Rights Holder: 国立大学法人熊本大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-090864
  • Filing Date: 2016-04-28