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Integrated understanding of the beta-lactam resistant mechanisms in mutations responsible for the beta-lactam resistance in oxacillin susceptible MRSA

Research Project

Project/Area Number 19K08960
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54030:Infectious disease medicine-related
Research InstitutionJichi Medical University

Principal Investigator

Watanabe Shinya  自治医科大学, 医学部, 准教授 (60614956)

Co-Investigator(Kenkyū-buntansha) 相羽 由詞  自治医科大学, 医学部, 助教 (60783694)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywordsメチシリン耐性黄色ブドウ球菌 / MRSA / 薬剤耐性菌 / βラクタム薬 / オキサシリン感性黄色ブドウ球菌 / 黄色ブドウ球菌 / ゲノム解析
Outline of Research at the Start

耐性遺伝子を持ちながら抗菌薬に感性を示す「ステルス型耐性菌」は、抗菌薬暴露により速やかに耐性化し、抗菌薬治療が失敗する危険性がある潜在的な耐性菌である。ステルス型耐性菌であるオキサシリン感性mecA陽性黄色ブドウ球菌(OS-MRSA)は、しばしば臨床分離され診療上問題となるが、そのβラクタム薬感性・耐性化メカニズムは全く解明されていない。本研究では、ゲノム間比較解析による臨床分離OS-MRSA株のβラクタム薬耐性関連変異の同定などを実施することで、OS-MRSAのβラクタム薬感性・耐性化の遺伝学的メカニズムを解明し、MRSAのβラクタム薬耐性の全容を明らかにする。

Outline of Final Research Achievements

Recently oxacillin-susceptible mecA-positive S. aureus (OS-MRSA) have been increasingly reported worldwide. OS-MRSA may be prone to generate the highly beta-lactam-resistant mutants following antibiotic selection due to mecA carriage, ultimately leading to beta-lactam treatment failure. The research aim is to clarify mechanisms of beta-lactam susceptibility and beta-lactam resistance acquisition by beta-lactam exposure in OS-MRSA. Genome analysis of 43 OS-MRSA revealed a high diversity of genetic background. 100 oxacillin resistant mutants generated by oxacillin exposure carried a total of 141 mutations in 46 genes and 8 intergenic regions. Among them, the mutations were most frequently identified in RNA polymerase genes (rpoBC). The mutations on rpoBC disrupted in vivo RNA synthesis and caused accumulation of ribonucleotide triphosphate and peptidoglycan precursors. It might affect oxacillin resistance in the mutants.

Academic Significance and Societal Importance of the Research Achievements

メチシリン耐性黄色ブドウ球菌(MRSA)は、院内感染の指標耐性菌のひとつであり、医療現場において監視が必要な耐性菌である。MRSAは、耐性遺伝子mecAを保有する。しかし、mecAを保有するにも関わらずβラクタム系抗菌薬であるオキサシリンに感性を示す「オキサシリン感性mecA陽性黄色ブドウ球菌(OS-MRSA)」が度々臨床分離される。OS-MRSAはメチシリン感性黄色ブドウ球菌と誤判定されてβラクタム薬治療が開始されると、そのβラクタム薬暴露により耐性化する可能性があることが臨床上の問題である。本研究課題では、OS-MRSAのβラクタム薬暴露による耐性化メカニズムの一端を明らかにした。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (20 results)

All 2022 2021 2020 2019

All Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (10 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Book (1 results)

  • [Journal Article] The Association Between Onset of Staphylococcal Non-menstrual Toxic Shock Syndrome With Inducibility of Toxic Shock Syndrome Toxin-1 Production2022

    • Author(s)
      Taki Yusuke、Watanabe Shinya、Sato’o Yusuke、Tan Xin-Ee、Ono Hisaya K.、Kiga Kotaro、Aiba Yoshifumi、Sasahara Teppei、Azam Aa Haeruman、Thitiananpakorn Kanate、Veeranarayanan Srivani、Li Feng-Yu、Zhang Yuancheng、Kawaguchi Tomofumi、Hossain Sarah、Maniruzzaman、Hu Dong-Liang、Cui Longzhu
    • Journal Title

      Frontiers in Microbiology

      Volume: 13 Pages: 765317-765317

    • DOI

      10.3389/fmicb.2022.765317

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interspecies Regulation Between Staphylococcus caprae and Staphylococcus aureus Colonized on Healed Skin After Injury2022

    • Author(s)
      Ogura Kohei、Furuya Hiroka、Takahashi Natsuki、Shibata Kana、Endo Maho、Watanabe Shinya、Cui Longzhu、Miyoshi-Akiyama Tohru、Okamoto Shigefumi、Ogai Kazuhiro、Sugama Junko
    • Journal Title

      Frontiers in Microbiology

      Volume: 13 Pages: 999-999

    • DOI

      10.3389/fmicb.2022.818398

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Complete Genome Sequencing of Mycobacterium heckeshornense Strain JMUB5695, Isolated from Necrotizing Granulomatous Lesions2021

    • Author(s)
      Katahira Katsuyuki、Watanabe Shinya、Wakamatsu Kentaro、Nagasawa Zenzo、Kawasaki Masayuki、Cui Longzhu
    • Journal Title

      Microbiology Resource Announcements

      Volume: 10 Issue: 27

    • DOI

      10.1128/mra.00141-21

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification and characterization of mutations responsible for the β-lactam resistance in oxacillin-susceptible mecA-positive Staphylococcus aureus2020

    • Author(s)
      Boonsiri Tanit、Watanabe Shinya、Tan Xin-Ee、Thitiananpakorn Kanate、Narimatsu Ryu、Sasaki Kosuke、Takenouchi Remi、Sato’o Yusuke、Aiba Yoshifumi、Kiga Kotaro、Sasahara Teppei、Taki Yusuke、Li Feng-Yu、Zhang Yuancheng、Azam Aa Haeruman、Kawaguchi Tomofumi、Cui Longzhu
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 16907-16907

    • DOI

      10.1038/s41598-020-73796-5

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of CRISPR-Cas13a-based antimicrobials capable of sequence-specific killing of target bacteria2020

    • Author(s)
      Kiga Kotaro、Tan Xin-Ee、Ibarra-Ch?vez Rodrigo、Watanabe Shinya、Aiba Yoshifumi、Sato’o Yusuke、Li Feng-Yu、Sasahara Teppei、Cui Bintao、Kawauchi Moriyuki、Boonsiri Tanit、Thitiananpakorn Kanate、Taki Yusuke、Azam Aa Haeruman、Suzuki Masato、Penad?s Jos? R.、Cui Longzhu
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 2934-2934

    • DOI

      10.1038/s41467-020-16731-6

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Association of mprF mutations with cross-resistance to daptomycin and vancomycin in methicillin-resistant Staphylococcus aureus (MRSA)2020

    • Author(s)
      Thitiananpakorn Kanate、Aiba Yoshifumi、Tan Xin-Ee、Watanabe Shinya、Kiga Kotaro、Sato’o Yusuke、Boonsiri Tanit、Li Feng-Yu、Sasahara Teppei、Taki Yusuke、Azam Aa Haeruman、Zhang Yuancheng、Cui Longzhu
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 16107-16107

    • DOI

      10.1038/s41598-020-73108-x

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Complete Genome Sequence of a Panton-Valentine Leukocidin-Negative Staphylococcus aureus Strain Isolated from a Patient with Pervasive Necrotizing Soft Tissue Infection2020

    • Author(s)
      Aiba Yoshifumi、Watanabe Shinya、Tsukahara Rieko、Umemoto Naoka、Thitiananpakorn Kanate、Boonsiri Tanit、Li Feng-Yu、Kiga Kotaro、Sato’o Yusuke、Tan Xin-Ee、Taki Yusuke、Azam Aa Haeruman、Zhang Yuancheng、Sasahara Teppei、Demitsu Toshio、Cui Longzhu
    • Journal Title

      Microbiology Resource Announcements

      Volume: 9 Issue: 23

    • DOI

      10.1128/mra.00295-20

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Composition and Diversity of CRISPR-Cas13a Systems in the Genus Leptotrichia2019

    • Author(s)
      Watanabe Shinya、Cui Bintao、Kiga Kotaro、Aiba Yoshifumi、Tan Xin-Ee、Sato’o Yusuke、Kawauchi Moriyuki、Boonsiri Tanit、Thitiananpakorn Kanate、Taki Yusuke、Li Fen-Yu、Azam Aa Haeruman、Nakada Yumi、Sasahara Teppei、Cui Longzhu
    • Journal Title

      Frontiers in Microbiology

      Volume: 10 Pages: 2838-2838

    • DOI

      10.3389/fmicb.2019.02838

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Probiotics Prevents Sensitization to Oral Antigen and Subsequent Increases in Intestinal Tight Junction Permeability in Juvenile?Young Adult Rats2019

    • Author(s)
      Tulyeu、Kumagai、Jimbo、Watanabe、Yokoyama、Cui、Osaka、Mieno、Yamagata
    • Journal Title

      Microorganisms

      Volume: 7 Issue: 10 Pages: 463-463

    • DOI

      10.3390/microorganisms7100463

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 毒素性ショック症候群を発症した黄色ブドウ球菌の毒素産生制御機構の解明.2021

    • Author(s)
      ○瀧 雄介,渡邊 真弥,佐藤 祐介,李 峰宇,Kanate Thitiananpakorn,XinEe Tan,相羽 由詞,氣駕 恒太朗,笹原 鉄平,崔 龍洙.
    • Organizer
      日本細菌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] CRISPR-Cas13 を用いた細菌遺伝子検査用抗菌カプシドの作製条件の最適化.2021

    • Author(s)
      ○西川 裕太郎,氣駕 恒太朗,渡邊 真弥,XinEe Tan,鈴木 貴子,下條 誉幸,崔 龍洙
    • Organizer
      日本細菌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Generation of phagemid-based CRISPR-Cas13 antimicrobials against MRSA.2021

    • Author(s)
      ○李 峰宇,氣駕 恒太朗,Xin-Ee Tan,渡邊 真弥,佐藤 祐介,相羽 由詞,Kanate Thitiananpakorn,瀧 雄介,笹原 鉄平,崔 龍洙
    • Organizer
      日本細菌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Oxacillin 感性 mecA 陽性黄色ブドウ球菌の β ラクタム薬 in vitro 高度耐性化機構の解析.2020

    • Author(s)
      ○渡邊 真弥,Tanit Boonsiri,Kanate Thitiananpakorn,XinEe Tan,相羽 由詞,佐藤 祐介,氣駕 恒太朗,瀧 雄介,笹原 鉄平, 崔 龍洙
    • Organizer
      第93回 日本細菌学会総会.
    • Related Report
      2019 Research-status Report
  • [Presentation] 毒素性ショック症候群を発症した黄色ブドウ球菌の毒素産生制御機構の解明2020

    • Author(s)
      瀧 雄介,渡邊 真弥,佐藤 祐介,李 峰宇,Kanate Thitiananpakorn,Tanit Boonsiri,相羽 由詞,氣駕 恒太朗, 笹原 鉄平,崔 龍洙
    • Organizer
      第93回 日本細菌学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Genetic mechanisms of high-level β-lactam-resistance in the mutants derived from oxacillin-susceptible mecA positive Staphylococcus aureus.2019

    • Author(s)
      ○Shinya Watanabe, Tanit Boonsiri, Kanate Thitiananpakorn, Yusuke Sato’o, Yoshifumi Aiba, Kotaro Kiga, Teppei Sasahara, Moriyuki Kawauchi, Aa Haeruman Azam, Feng-Yu Li, XinEe Tan and Longzhu Cui.
    • Organizer
      Staphylococcal Diseases, Gordon Research Conference 2019.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Genetic Analysis of Highly β-lactam-resistant Mutants Generated from OS-MRSA2019

    • Author(s)
      〇Tanit Boonsiri,渡邊真弥,Kanate Thitiananpakorn,佐藤祐介,相羽由詞,氣駕恒太朗,笹原鉄平, 李峰宇,Xin Ee Tan,崔龍洙
    • Organizer
      第92回 日本細菌学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 〇瀧雄介,渡邊真弥,佐藤祐介,李峰宇,Kanate Thitiananpakorn,Tanit Boonsiri,相羽由詞,氣駕恒太朗,崔龍洙2019

    • Author(s)
      毒素性ショック症候群を発症した黄色ブドウ球菌の毒素産生制御機構の解明
    • Organizer
      第92回 日本細菌学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 緑膿菌に広く感染するファージの分離・同定2019

    • Author(s)
      〇渡邊真弥,李峰宇,氣駕恒太朗,相羽由詞,佐藤祐介,Xin Ee Tan,河内護之,Tanit Boonsiri,Kanate Thitiananpakorn,崔龍洙
    • Organizer
      第92回 日本細菌学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 試験管内で選択したカナマイシン耐性結核菌のマウスに対する病原性解析2019

    • Author(s)
      ○渡邊真弥
    • Organizer
      第92回 細菌学会総会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Book] 創薬研究者・アカデミア研究者が知っておくべき最新の免疫学とその応用技術.第10節 薬剤耐性(AMR)菌と新規抗菌治療薬開発の現状と展望.2021

    • Author(s)
      渡邊真弥、氣駕恒太朗、崔龍洙
    • Total Pages
      598
    • Publisher
      技術情報協会
    • ISBN
      4861048567
    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2023-12-25  

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