Education 【 display / non-display 】

Education 【 display / non-display 】

• 1985

  -

  1987

  北海道大学大学院   理学研究科   化学専攻  

• 1981

  -

  1985

  Hokkaido University   Faculty of Science   Department of Chemistry  

Degree 【 display / non-display 】

Degree 【 display / non-display 】

• The University of Tokyo   Ph.D. (Pharmaceutical Science)

• Hokkaido University   M.Sc

Research Experience 【 display / non-display 】

Research Experience 【 display / non-display 】

• 2013.09

  -

  Now

  Sapporo Medical University   School of Medicine, Dept.of Microbiology   教授

  教授

• 2007.04

  -

  2013.08

  Sapporo Medical University   School of Medicine, Dept.of Microbiology   准教授

  准教授

• 2004.02

  -

  2007.03

  Sapporo Medical University   School of Medicine, Dept.of Microbiology   助教授

  助教授

• 2000.05

  -

  2004.01

  Sapporo Medical University   School of Medicine, Dept.of Microbiology   講師

  講師

• 1997.10

  -

  2000.04

  株式会社エイチ・エス・ピー研究所   副主任研究員

  副主任研究員

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Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

• 　

  　

  　

  臨床ストレス応答学会

• 　

  　

  　

  Japanese Society for Virology

• 　

  　

  　

  Japan Pseudomonas aeruginosa Society

• 　

  　

  　

  米国微生物学会

• 　

  　

  　

  JAPANESE SOCIETY OF CHEMOTHERAPY

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Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Immunology  

• Life sciences   Virology  

• Life sciences   Bacteriology  

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Sapporo Medical University   School of Medicine, Dept.of Microbiology   Professor  

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• Immunostimulatory activity of lipoteichoic acid with three fatty acid residues derived from <i>Limosilactobacillus antri</i> JCM 15950 ^T

  Shino Yamasaki-Yashiki, Tsukasa Shiraishi, Mai Gyobu, Haruna Sasaki, Jun Kunisawa, Shin-ichi Yokota, Yoshio Katakura

  Applied and Environmental Microbiology ( American Society for Microbiology )   2024.09

  　View Summary

  ABSTRACT Some strains of lactic acid bacteria can regulate the host’s intestinal immune system. Bacterial cells and membrane vesicles (MVs) of Limosilactobacillus antri JCM 15950 ^T promote immunoglobulin A (IgA) production in murine Peyer’s patch cells via toll-like receptor (TLR) 2. This study aimed to investigate the role of lipoteichoic acid (LTA), a ligand of TLR2, in the immunostimulatory activity of these bacterial cells and their MVs. LTA extracted from bacterial cells was purified through hydrophobic interaction chromatography and then divided into fractions LTA1 and LTA2 through anion-exchange chromatography. LTA1 induced greater interleukin (IL)-6 production from macrophage-like RAW264 cells than LTA2, and the induced IL-6 production was suppressed by TLR2 neutralization using an anti-TLR2 antibody. The LTAs in both fractions contained two hexose residues in the glycolipid anchor; however, LTA1 was particularly rich in triacyl LTA. The free hydroxy groups in the glycerol phosphate (GroP) repeating units were substituted by d -alanine ( d -Ala) and α-glucose in LTA1, but only by α-glucose in LTA2. The dealanylation of LTA1 slightly suppressed IL-6 production in RAW264 cells, whereas deacylation almost completely suppressed IL-6 production. Furthermore, IL-6 production induced by dealanylated LTA1 was markedly higher than that induced by dealanylated LTA2. These results indicated that the critical moieties for the immunostimulatory activity of L. antri -derived LTA were the three fatty acid residues rather than the substitution with d -Ala in GroP. LTA was also detected in MVs, suggesting that the triacyl LTA, but not the diacyl LTA, translocated to the MVs and conferred immunostimulatory activity. IMPORTANCE Some lactic acid bacteria activate the host intestinal immune system via toll-like receptor (TLR) 2. Lipoteichoic acid (LTA) is a TLR2 ligand; however, the moieties of LTA that determine its immunostimulatory activity remain unclear because of the wide diversity of LTA partial structures. We found that Limosilactobacillus antri JCM 15950 ^T has three types of LTAs (triacyl, diacyl, and monoacyl LTAs). Specifically, structural analysis of the LTAs revealed that triacyl LTA plays a crucial role in immunostimulation and that the fatty acid residues are essential for the activity. The three acyl residues are characteristic of LTAs from many lactic acid bacteria, and our findings can explain the immunostimulatory mechanisms widely exhibited by lactic acid bacteria. Furthermore, the immunostimulatory activity of membrane vesicles released by L. antri JCM 15950 ^T is due to the transferred LTA, demonstrating a novel mechanism of membrane vesicle-mediated immunostimulation.

  DOI

• Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.

  Kazuki Yamamoto, Toyotaka Sato, Aili Hao, Kenta Asao, Rintaro Kaguchi, Shintaro Kusaka, Radhakrishnam Raju Ruddarraju, Daichi Kazamori, Kiki Seo, Satoshi Takahashi, Motohiro Horiuchi, Shin-Ichi Yokota, Seok-Yong Lee, Satoshi Ichikawa

  Nature communications   15 ( 1 ) 5085 - 5085  2024.06  [International journal]

  　View Summary

  MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.

  DOI PubMed

• Traces of pandemic fluoroquinolone-resistant Escherichia coli clone ST131 transmitted from human society to aquatic environments and wildlife in Japan

  Toyotaka Sato, Kojiro Uemura, Mitsuru Yasuda, Aiko Maeda, Toshifumi Minamoto, Kazuki Harada, Michiyo Sugiyama, Shiori Ikushima, Shin-ichi Yokota, Motohiro Horiuchi, Satoshi Takahashi, Testuo Asai

  One Health ( Elsevier BV )  18   100715  2024.06  [Refereed]

  DOI

• The clarithromycin-binding proteins NIPSNAP1 and 2 regulate cytokine production through mitochondrial quality control.

  Soh Yamamoto, Noriko Ogasawara, Yukari Mitsuhashi, Kenichi Takano, Shin-Ichi Yokota

  Scientific reports   14 ( 1 ) 2354 - 2354  2024.01  [International journal]

  　View Summary

  The mechanism underlying the anti-inflammatory effect of macrolide antibiotics, such as clarithromycin (CAM), remains to be clarified. The CAM-binding proteins 4-nitrophenylphosphatase domain and non-neuronal synaptosomal associated protein 25 (SNAP25)-like protein homolog (NIPSNAP) 1 and 2 are involved in the immune response and mitochondrial homeostasis. However, the axis between CAM-NIPSNAP-mitochondria and Toll-like receptor (TLR) and their molecular mechanisms remain unknown. In this study, we sought to elucidate the relationship between mitochondrial homeostasis mediated by NIPSNAP1 and 2 and the immunomodulatory effect of CAM. NIPSNAP1 or 2 knockdown (KD) by RNA interference impaired TLR4-mediated interleukin-8 (IL-8) production. Similar impairment was observed upon treatment with mitochondrial function inhibitors. However, IL-8 secretion was not impaired in NIPSNAP1 and 2 individual knockout (KO) and double KO (DKO) cells. Moreover, the oxygen consumption rate (OCR) in mitochondria measured using a flex analyzer was significantly reduced in NIPSNAP1 or 2 KD cells, but not in DKO cells. CAM also dose-dependently reduced the OCR. These results indicate that CAM suppresses the IL-8 production via the mitochondrial quality control regulated by temporary functional inhibition of NIPSNAP1 and 2. Our findings provide new insight into the mechanisms underlying cytokine production, including the TLR-mitochondria axis, and the immunomodulatory effects of macrolides.

  DOI PubMed

• Affinity of β-Lactam Antibiotics for Neisseria gonorrhoeae Penicillin-Binding Protein 2 Having Wild, Cefixime-Reduced-Susceptible, and Cephalosporin (Ceftriaxone)-Resistant penA Alleles.

  Yoshiki Hiyama, Soh Yamamoto, Toyotaka Sato, Noriko Ogasawara, Naoya Masumori, Satoshi Takahashi, Shin-Ichi Yokota

  Microbial drug resistance (Larchmont, N.Y.)    2024.01  [International journal]

  　View Summary

  Multidrug-resistant Neisseria gonorrhoeae is a serious concern worldwide. Resistance to β-lactam antibiotics occurs through mutations in penicillin-binding proteins (PBPs), acquisition of β-lactamases, and alteration of antibiotic penetration. Mosaic structures of penA, which encodes PBP2, play a major role in resistance to β-lactams, especially cephalosporins. Ceftriaxone (CRO) is recognized as the only satisfiable antibiotic for the treatment of gonococcal infections; however, CRO-resistant isolates have emerged in the community. Here, we examined the affinity of β-lactam antibiotics for recombinant PBP2 in a competition assay using fluorescence-labeled penicillin. We found no or little difference in the affinities of penicillins and meropenem (MEM) for PBP2 from cefixime (CFM)-reduced-susceptible strain and cephalosporin-resistant strain. However, the affinity of cephalosporins, including CRO, for PBP2 from the cephalosporin-resistant strain was markedly lower than that for PBP2 from the CFM-reduced-susceptible-resistant strain. Notably, piperacillin (PIP) showed almost the same affinity for PBP2 from penicillin-susceptible, CFM-reduced-susceptible, and cephalosporin (including CRO)-resistant strains. Thus, PIP/tazobactam and MEM are candidate antibiotics for the treatment of CRO-resistant/multidrug-resistant N. gonorrhoeae.

  DOI PubMed

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Books and Other Publications 【 display / non-display 】

Books and Other Publications 【 display / non-display 】

• 標準微生物学

  錫谷, 達夫, 松本, 哲哉( Part： Contributor, エンドトキシン（リポ多糖）)

  医学書院  2024.02 ISBN: 9784260053440

• 図解微生物学・感染症・化学療法

  藤井, 暢弘, 山本, 友子( Part： Contributor, 感染症と生体防御，化学療法（抗菌薬）)

  南山堂  2020.10 ISBN: 9784525751326

• エース薬理学

  安西, 尚彦, 安藤, 仁, 浅井, 聡, 金井, 好克( Part： Contributor, 抗菌薬)

  南山堂  2020.08 ISBN: 9784525140717

• シンプル微生物学（改訂第6版）

  横田伸一( Part： Contributor, らせん菌群)

  南江堂  2018

• 病原微生物学 : 基礎と臨床

  荒川, 宜親, 神谷, 茂, 柳, 雄介( Part： Contributor, グラム陰性好気性桿菌)

  東京化学同人  2014.12 ISBN: 9784807908271

Misc 【 display / non-display 】

Misc 【 display / non-display 】

• 薬剤耐性菌感染症における感染部位特異的治療法の可能性評価

  佐藤 豊孝, 高橋 聡, 横田 伸一

  日本化学療法学会雑誌 ( (公社)日本化学療法学会 )  72 ( 1 ) 114 - 114  2024.01

• 薬剤耐性菌感染症における感染部位特異的治療法の可能性評価

  佐藤 豊孝, 高橋 聡, 横田 伸一

  日本化学療法学会雑誌 ( (公社)日本化学療法学会 )  72 ( 1 ) 114 - 114  2024.01

• 伴侶動物由来フルオロキノロン耐性大腸菌の特徴とヒトとの伝播の可能性の評価

  佐藤 豊孝, 上村 幸二朗, 高橋 聡, 横田 伸一

  日本化学療法学会雑誌 ( (公社)日本化学療法学会 )  71 ( 4 ) 503 - 503  2023.07

• 伴侶動物由来フルオロキノロン耐性大腸菌の特徴とヒトとの伝播の可能性の評価

  佐藤 豊孝, 上村 幸二朗, 高橋 聡, 横田 伸一

  日本感染症学会総会・学術講演会・日本化学療法学会学術集会合同学会プログラム・抄録集 ( 日本感染症学会・日本化学療法学会 )  97回・71回   O - 294  2023.03

• Candida albicansは尿糖の存在下で増殖促進に加えてアゾール系やフルシトシンの抗真菌薬の感受性が低下する。

  桧山佳樹, 桧山佳樹, 桧山佳樹, 佐藤豊孝, 佐藤豊孝, 佐藤豊孝, 高橋聡, 舛森直哉, 横田伸一

  日本感染症学会東日本地方会学術集会・日本化学療法学会東日本支部総会合同学会プログラム・抄録集   71st-69th  2022

  J-GLOBAL

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Awards 【 display / non-display 】

Awards 【 display / non-display 】

• 奨励研究賞

  2017   マクロライド新作用研究会  

  Winner： 横田 伸一

• 第6回小林六造記念ヘリコバクター賞

  2010   日本ヘリコバクター学会  

  Winner： 横田 伸一

• 黒住医学研究振興財団研究助成

  2008  

  Winner： 横田 伸一

• 金原一郎記念医学医療振興財団研究助成

  2005  

• The Ichiro Kanehara Foundation

  2005  

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Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• Apilactobacillus kosoi 10HT 乳酸菌株由来新奇リポテイコ酸の構造および免疫賦活活性の構造活性相関の解明

  Project Year :

  2023.04

  -

  2025.03

   

  横田伸一, 白石宗

• Cell signiling pathway of Toll-like receptor agonists with low activity

  Grant-in-Aid for Scientific Research (B)

  Project Year :

  2020.04

  -

  2023.03

   

  横田 伸一, 小笠原 徳子, 山本 聡, 白石 宗, 永島 裕之, 佐藤 豊孝

  　View Summary

  グラム陽性菌リポテイコ酸（LTA）のIL-8産生誘導能に関して、ヒト結腸癌由来細胞であるCaco-2細胞は、TLR4アゴニストのリポ多糖（LPS）、TLR2/TLR1アゴニストのPam3CSKや３種の乳酸菌LTAにはほとんど応答しないのに対して、黄色ブドウ菌LTAとTLR2/TLR6アゴニストでのみIL-8産生が認められるという特異なサイトカイン応答を示した。検討した3種の乳酸菌LTAと黄色ブドウ球菌LTAの親水性領域はD-アラニン置換のあるグリセロールリン酸ポリマーで共通している。一方、アンカー糖脂質の脂質成分として、黄色ブドウ球菌ではC18:0と分岐脂肪酸であるanteiso-C17:0、anteiso-C15:0から構成され、乳酸菌では不飽和脂肪酸C18:1(n-9)とC16:0、さらにガセリ菌以外ではシクロプロパン環を有するC19:cyが含まれていた。脂質の組成の違いがLTAのCaco-2細胞によるLTAの認識に違いを与えていることが示唆された。 低活性TLRアゴニストの情報伝達とマクロライド系抗菌薬が持つ免疫調節活性の情報伝達系の関連性に関して、クラリスロマイシン結合タンパク質として同定していたNIP-SNAP-1, 2のCrispr-Cas9によるノックアウト（KO）細胞株とsiRNAによるノックダウン（KD）細胞株を作製した。グラム陰性菌リポ多糖（LPS）刺激によるIL-8, IL-6産生誘導は、KDで著明に低下したが、KOでは変化が認められなく、挙動に違いが認められた。NIP-SNAP-1, 2のサイトカイン誘導との関連は示唆されたが、KOにおける挙動では何らかのサルベージ経路が働いているとの仮説を立て、RNseq解析を行い、それに関わる因子の同定に着手した

• 遊離脂肪酸の病原細菌への効果の解明と熱傷局所療法への応用の研究

  基盤研究(C)

  Project Year :

  2017.04

  -

  2023.03

   

  上村 修二, 横田 伸一, 文屋 尚史, 白石 宗

  　View Summary

  黄色ブドウ球菌3株(標準株、市中感染型MRSA、病院感染型MRSA)に対する以下の8種類の脂肪酸：C14:1(cis-9)、C16:0、C16:1(cis-9)、C16:1(trans-9)、C18:0、C18:1(cis-9)、C18:2(cis-9、12)、C20:1(cis-11)のMICを測定した。 脂肪酸単独による検証ではC14:1(cis-9)、C16:1(cis-9)で抗菌活性を認めた。Gentamicin併用ではC14:1(cis-9)、C16:1(cis-9)、C16:1(trans-9)、C18:2(cis-9,12)で増強作用を認めた。Fradiomycin併用ではC14:1(cis-9)、C16:1(cis-9)、C16:1(trans-9)、C18:2(cis-9,12)で増強作用を認めた。Sulfadiazine silver併用では増強作用を認めた脂肪酸はなかった。 本研究でC14:1(cis-9)、C16:1(cis-9)は単独での抗菌活性に加えて、アミノグリコシド系への増強効果も期待できることがわかった。GentamicinとFradiomycinは通常臨床で使用している軟膏に含有されている抗生剤であるため、適切な脂肪酸を加えることで更に抗菌作用を強められる可能性が示唆された。現在、熱傷創で黄色ブドウ球菌と並んで問題となっている緑膿菌に対しても抗菌活性や抗生剤の増強効果を検証中である。

• Usefulness of disease-specific microRNA for respiratory syncytial virus induced lower respiratory tract inflammation

  Grant-in-Aid for Young Scientists (B)

  Project Year :

  2016.04

  -

  2018.03

   

  Yamamoto Keisuke, HIMI Tetsuo, YOKOTA Shin-ichi, Takano Kenichi, KUROSE Makoto, KAMEKURA Ryuta, OHKUNI Tsuyoshi, OGASAWARA Noriko, YAMAMOTO Soh

  　View Summary

  (1)Clarithromycin (CAM) as a treatment of RSV infection and (2)disease-specific microRNA as an index of disease evaluation were examined.CAM treatment led to a significant reduction in RSV-mediated IL-8, CCL5, IFN-βand -λ production.Furthermore,IFN-β promoter activity (activated by poly I:C and RSV infection) was significantly reduced after treatment with CAM.CAM also inhibited IRF-3 dimerization and subsequent translocation to the nucleus.
  RSV infection-specific secreted miRNAs were identified. Housekeeping gene of nasal secreted miRNA was identified.

• Clarification of drug resistance of mucoid type Streptococcus pneumoniae

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2015.04

  -

  2018.03

   

  Miyamoto Atsushi

  　View Summary

  We obtained 51 mucoid strains from 1,061 Streptococcus pneumoniae clinical isolates collected in Hokkaido Prefecture, Japan. We evaluated biofilm formation, minimum biofilm eradication concentration of various antimicrobials, and growth rate. Significant differences between mucoid and non-mucoid strains were not observed. On the other hand, we found that Natto peptide, which is from a Japanese soy bean fermented food, showed specific bactericidal activity against S. pneumoniae, and Bacillus subtilis group of Bacillus genus. We clarified that its mechanism was failure of cell separation during cell division in S. pneumoniae. The Natto peptide showed similar antimicrobial activity against mucoid, non-mucoid, antimicrobial susceptible, and multidrug resistant strains of S. pneumoniae.

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