Lysocin E is a new antibiotic that targets menaquinone in the bacterial membrane

• Published in: Nature chemical biology Vol. 11; no. 2; pp. 127 - 133
• Main Authors: Hamamoto, Hiroshi, Urai, Makoto, Ishii, Kenichi, Yasukawa, Jyunichiro, Paudel, Atmika, Murai, Motoki, Kaji, Takuya, Kuranaga, Takefumi, Hamase, Kenji, Katsu, Takashi, Su, Jie, Adachi, Tatsuo, Uchida, Ryuji, Tomoda, Hiroshi, Yamada, Maki, Souma, Manabu, Kurihara, Hiroki, Inoue, Masayuki, Sekimizu, Kazuhisa
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2015; Nature Publishing Group
• Subjects: 101/58; 38/70; 45/43; 631/154/1435/2417; 631/326/41; 631/92/555; 631/92/611; 64/60; Animals; Anti-Bacterial Agents - isolation & purification; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Bacteria; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bacteriolysis - drug effects; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Bombyx - microbiology; Bombyx mori; Cell Biology; Cell culture; Cell Membrane - drug effects; Cell Membrane - metabolism; Chemistry; Chemistry/Food Science; Disease Models, Animal; Drug Discovery - methods; Drug therapy; Gram-Positive Bacteria - drug effects; Gram-Positive Bacteria - genetics; Gram-Positive Bacteria - metabolism; Invertebrates; Lysobacter - metabolism; Mammals; Membrane Potentials - drug effects; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Mode of action; Molecular Structure; Mortality; Peptides, Cyclic - isolation & purification; Peptides, Cyclic - pharmacology; Peptides, Cyclic - therapeutic use; Staphylococcal Infections - drug therapy; Staphylococcus aureus - drug effects; Staphylococcus aureus - genetics; Staphylococcus aureus - metabolism; Vitamin K 2 - antagonists & inhibitors; Vitamin K 2 - metabolism
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1710

A family of cyclic lipopeptide natural products named lysocins was isolated from a soil bacteria sample and was found to exhibit antimicrobial actions. Genetic and biochemical evidence showed that lysocin E targets bacterial menaquinone. 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.