Elucidation of macrolide resistance mechanism and virulence of Streptococcus pyogenes focused on phage DNA

• Project/Area Number: 16K08782
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bacteriology (including mycology)
• Research Institution: Nagoya City University
• Principal Investigator: Hasegawa Tadao 名古屋市立大学, 大学院医学研究科, 教授 (10314014)
• Co-Investigator(Kenkyū-buntansha): 井坂 雅徳 名古屋市立大学, 大学院医学研究科, 助教 (40336673) ; 立野 一郎 名古屋市立大学, 大学院医学研究科, 講師 (50311642)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: A群レンサ球菌 / マクロライド / ファージ / mef(A) / msr(D) / 薬剤耐性 / 病原性 / 病原因子 / 二成分制御系 / 劇症型感染症

Outline of Final Research Achievements

We elucidated the macrolide resistance mechanism and virulence of Streptococcus pyogenes focused on phage DNA.
The roles of mef(A)/mef(E) genes that encode drug efflux pump in macrolide resistance are not much; however, those of msr(D) genes that exit downstream of mef(A)/mef(E) genes play more important roles. In addition, the degree of macrolide resistance is correlated with the nucleotide difference of msr(D) genes. Finally, macrolide resistance is suggested to be under control of two-component regulatory systems that sense outer signals.

Academic Significance and Societal Importance of the Research Achievements

今回の結果は従来マクロライド耐性メカニズムの一つとして定説であったmef(A)/mef(E)による薬剤の排出メカニズムの関与は少なく、mef(A)/mef(E)遺伝子それぞれのゲノム直下にあるmsr(D)の重要性を確立したのみならず、それぞれのmsr(D)の塩基配列の違いが菌のマクロライド耐性の度合いと相関することを世界で初めて明らかにしたことが学術的な意義である。マクロライドは世界で広く使用されている抗生物質のひとつであり、薬剤耐性を克服するうえでその真の耐性メカニズムを明らかにしたことは今後の創薬にも貢献することが期待される。

Research Products

• [Journal Article] Homologous role of CovRS two-component regulatory system in NAD+ -glycohydrolase activity in Streptococcus dysgalactiae subsp. equisimilis as in Streptococcus pyogenes. (2019)
  • Author(s): Hasegawa T, Matsumoto M, Hata N, Yano H, Isaka M, Tatsuno I.
  • Journal Title: APMIS Volume: 127 Issue: 2 Pages: 87-92
  • DOI: 10.1111/apm.12914
  • Peer Reviewed / Open Access
• [Journal Article] Functional Predominance of msr(D), Which Is More Effective as mef(A)-Associated Than mef(E)-Associated, Over mef(A)/mef(E) in Macrolide Resistance in Streptococcus pyogenes (2018)
  • Author(s): Tatsuno Ichiro、Isaka Masanori、Masuno Katsuaki、Hata Nanako、Matsumoto Masakado、Hasegawa Tadao
  • Journal Title: Microbial Drug Resistance Volume: in press Issue: 8 Pages: 1089-1097
  • DOI: 10.1089/mdr.2017.0277
  • Peer Reviewed
• [Journal Article] Characterization of clinically isolated Streptococcus pyogenes from balanoposthitis patients with special emphasis on emm89 isolates. (2017)
  • Author(s): Hasegawa T, Hata N, Matsui H, Isaka M, Tatsuno I
  • Journal Title: J. Med. Microbiol. Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] A群レンサ球菌におけるmef(A), mef(E)マクロライド耐性システムの解析 (2017)
  • Author(s): 長谷川忠男、松本昌門、松井秀之、井坂雅徳、立野一郎
  • Organizer: 第54回日本細菌学会中部支部総会