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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Bacterial Agents / isolation & purification
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Anti-Bacterial Agents / pharmacology*
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Anti-Bacterial Agents / therapeutic use
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Bacteriolysis / drug effects
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Bombyx / microbiology
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Cell Membrane / drug effects*
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Cell Membrane / metabolism
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Disease Models, Animal
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Drug Discovery / methods*
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Gram-Positive Bacteria / drug effects*
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Gram-Positive Bacteria / genetics
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Gram-Positive Bacteria / metabolism
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Lysobacter / metabolism
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Membrane Potentials / drug effects
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Mice
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Mice, Inbred ICR
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Microbial Sensitivity Tests
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Molecular Structure
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Peptides, Cyclic / isolation & purification
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Peptides, Cyclic / pharmacology*
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Peptides, Cyclic / therapeutic use
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Staphylococcal Infections / drug therapy
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Staphylococcus aureus / drug effects
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Staphylococcus aureus / genetics
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Staphylococcus aureus / metabolism
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Vitamin K 2 / antagonists & inhibitors*
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Vitamin K 2 / metabolism
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Peptides, Cyclic
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lysocin E
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Vitamin K 2