title: Lysocin E is a new antibiotic that targets menaquinone in the bacterial membrane.
abstract: 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.
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.identifier: 0000000193157442
authors.initials: H
authors.lastname: Hamamoto
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Urai
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Jyunichiro
authors.initials: J
authors.lastname: Yasukawa
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Atmika
authors.initials: A
authors.lastname: Paudel
authors.affiliation: Laboratory of Synthetic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Murai
authors.affiliation: Laboratory of Synthetic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kaji
authors.affiliation: Laboratory of Synthetic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kuranaga
authors.affiliation: Department of Drug Discovery and Evolution, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hamase
authors.affiliation: Department of Pharmacy, Graduate School of Pharmacy, Yasuda Women's University, Hiroshima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Katsu
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Adachi
authors.affiliation: Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Uchida
authors.affiliation: Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
authors.affiliation: 1] Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. [2] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Yamada
authors.affiliation: MASIS Inc., Aomori, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Souma
authors.affiliation: 1] Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. [2] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.affiliation: Laboratory of Synthetic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Sekimizu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001433:Bacteriolysis / Q000187:drug effects; D012831:Bombyx / Q000382:microbiology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000379:methods*; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D053528:Lysobacter / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D024482:Vitamin K 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010456:Peptides, Cyclic; C000597008:lysocin E; D024482:Vitamin K 2