To obtain therapeutically effective new antibiotics, we first searched for bacterial culture supernatants with antimicrobial activity in vitro and then performed a secondary screening using the silkworm infection model. Through further purification of the in vivo activity, we obtained a compound with a previously uncharacterized structure and named it 'lysocin E'. Lysocin E interacted with menaquinone in the bacterial membrane to achieve its potent bactericidal activity, a mode of action distinct from that of any other known antibiotic, indicating that lysocin E comprises a new class of antibiotic. This is to our knowledge the first report of a direct interaction between a small chemical compound and menaquinone that leads to bacterial killing. Furthermore, lysocin E decreased the mortality of infected mice. To our knowledge, lysocin E is the first compound identified and purified by quantitative measurement of therapeutic effects in an invertebrate infection model that exhibits robust in vivo effects in mammals.

  • Compound C75H116N20O20

    Lysocin E

  • Compound C75H118N20O21

    Linearized lysocin E

  • Compound C75H118N20O20 18O

    18O-Labeled linearized lysocin E

  • Compound C75H120N20O20

    Reduced lysocin E

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This study was supported by a grant from Genome Pharmaceuticals Institute Co., Ltd. for K.S., the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) for K.S., a Grant-in-Aid for Young Scientists (A; 24689008) for H.H., a Grant-in-Aid for Scientific Research (25460036) for T. Katsu from Japan Society for the Promotion of Science (JSPS), a Grant-in-Aid for Scientific Research on Innovative Areas–Chemical Biology of Natural Products to K.S. (24102510) and to H.H. (26102714) from MEXT, and it was supported in part by a Grant-in-Aid for JSPS Fellows (24-11042) for K.I. from JSPS and the Japan Science and Technology Agency (JST) A-STEP (High-Risk Challenging Type). We thank A. Noguchi, F. Aihara and S. Nishida (Genome Pharmaceutical Institute, Co., Ltd.) for screening and production of lysocin E. We thank K. Sakamoto (Hirosaki University) for advice regarding the menaquinone analysis. We thank M. Hyodo (Okayama University), K. Kyogoku (University of Tokyo) and Y. Matsuzawa (Genome Pharmaceutical Institute, Co., Ltd.) for technical assistance. We thank Shiseido Co. Ltd. for their technical support in 2D-HPLC analyses.

Author information

Author notes

    • Makoto Urai

    Present address: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.

    • Hiroshi Hamamoto
    • , Makoto Urai
    •  & Kenichi Ishii

    These authors contributed equally to this work.


  1. Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

    • Hiroshi Hamamoto
    • , Makoto Urai
    • , Kenichi Ishii
    • , Jyunichiro Yasukawa
    • , Atmika Paudel
    • , Jie Su
    • , Tatsuo Adachi
    •  & Kazuhisa Sekimizu
  2. Laboratory of Synthetic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

    • Motoki Murai
    • , Takuya Kaji
    • , Takefumi Kuranaga
    •  & Masayuki Inoue
  3. Department of Drug Discovery and Evolution, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

    • Kenji Hamase
  4. Department of Pharmacy, Graduate School of Pharmacy, Yasuda Women's University, Hiroshima, Japan.

    • Takashi Katsu
  5. Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.

    • Ryuji Uchida
    •  & Hiroshi Tomoda
  6. Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

    • Maki Yamada
    •  & Hiroki Kurihara
  7. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.

    • Maki Yamada
    •  & Hiroki Kurihara
  8. MASIS Inc., Aomori, Japan.

    • Manabu Souma


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H.H. performed screening and purification, chemical structure analysis, mechanism analysis, acute toxicity analysis and manuscript drafting. M.U. performed chemical structure analysis and mechanism analysis, and drafted the supplementary results. K.I. performed bacterial genetic analysis, mechanism analysis and manuscript drafting. J.Y. performed bacterial genetic analysis and mechanism analysis. A.P. performed screening and purification and mechanism analysis. M.M., T. Kaji, T. Kuranaga and M.I. critically discussed and confirmed the lysocin E chemical structure. K.H. performed chemical structure analysis. T. Katsu and J.S. performed mechanism analysis. T.A. performed bacterial genetic analysis. R.U. performed analysis of nosokomycin A. H.T. performed analysis of nosocomycin A and critically revised the article for important intellectual content. M.Y. and H.K. performed acute toxicity analysis. M.S. performed chemical structure analysis. K.S. critically revised the article for important intellectual content and final approval of the article.

Competing interests

K.S. is a consultant for Genome Pharmaceutical Institute Co., Ltd.

Corresponding author

Correspondence to Kazuhisa Sekimizu.

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