lysocin-e and Disease-Models--Animal

　The emergence of antimicrobial resistant (AMR) bacteria has become a serious threat to public health. It is important that we find a mechanistically novel antibiotic to combat AMR. However, finding compounds which are both therapeutically effective and safe is difficult in the development of antibiotics. To solve these problems, we have focused on the silkworm model, which is economical and poses fewer ethical issues, as a means to evaluate the therapeutic effectiveness of test compounds in early stages of antibiotic development. Actually, the silkworm has pharmacokinetic parameters similar to mammals, and we revealed that antibiotics showed ED

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Bombyx; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Mice; Peptides, Cyclic

In this symposium, we reported the identification and mechanistic analysis of a novel antibiotic named lysocin E. Lysocin E was identified by screening for therapeutic effectiveness in a silkworm Staphylococcus aureus infection model. The advantages of the silkworm infection model for screening and purification of antibiotics from the culture supernatant of soil bacteria are: 1) low cost; 2) no ethical issues; 3) convenient for evaluation of the therapeutic effectiveness of antibiotics; and 4) pharmacokinetics similar to those of mammals. Lysocin E has remarkable features compared with known antibiotics such as a novel mechanism of action and target. Here, we summarize our reports presented in this symposium.

Topics: Animals; Anti-Bacterial Agents; Bombyx; Disease Models, Animal; Drug Evaluation, Preclinical; Peptides, Cyclic; Staphylococcal Infections

Development of novel medicines is an important responsibility of researchers in the field of pharmaceutical sciences. However, the discovery of new therapeutically effective without side effects is not an easy job. I think the limiting step of drug discovery is the process of evaluating the therapeutic effects of candidate drugs. To overcome this problem, I would like to propose a novel approach, "drug discovery with silkworms".

Topics: Animals; Anti-Bacterial Agents; Bombyx; Diabetes Mellitus; Disease Models, Animal; Drug Discovery; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Models, Animal; Peptides, Cyclic; Pharmacokinetics; Staphylococcal Infections; Virulence

New antimicrobials with novel mechanisms need to be developed to combat antimicrobial-resistant pathogenic bacteria. The current authors recently reported discovery of a new antibiotic named "Lysocin E". Lysocin E was identified using a silkworm model of bacterial infection. The current review discusses the advantages of using a silkworm model of bacterial infection to identify and develop therapeutically efficacious antimicrobials. This review also discusses the discovery of lysocin E and its novel mechanism of action.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Bombyx; Disease Models, Animal; Drug Discovery; Drug Resistance, Multiple, Bacterial; Humans; Larva; Molecular Structure; Peptides, Cyclic; Species Specificity

Lysocin E is a lipopeptide with antibiotic activity against methicillin-resistant Staphylococcus aureus. For unclear reasons, the antibacterial activity of lysocin E in a mouse systemic infection model is higher than expected from in vitro results, and the in vitro activity is enhanced by addition of bovine serum. Here, we confirm that serum from various species, including humans, increases lysocin E antimicrobial activity, and identify apolipoprotein A-I (ApoA-I) as an enhancing factor. ApoA-I increases the antibacterial activity of lysocin E when added in vitro, and the antibiotic displays reduced activity in ApoA-I gene knockout mice. Binding of ApoA-I to lysocin E is enhanced by lipid II, a cell-wall synthesis precursor found in the bacterial membrane. Thus, the antimicrobial activity of lysocin E is potentiated through interactions with host serum proteins and microbial components.

Topics: Animals; Anti-Bacterial Agents; Apolipoprotein A-I; Disease Models, Animal; Female; Lipopeptides; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Microbial Sensitivity Tests; Peptides, Cyclic; Staphylococcal Infections

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.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Bacteriolysis; Bombyx; Cell Membrane; Disease Models, Animal; Drug Discovery; Gram-Positive Bacteria; Lysobacter; Membrane Potentials; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Molecular Structure; Peptides, Cyclic; Staphylococcal Infections; Staphylococcus aureus; Vitamin K 2