Advantages of the Silkworm As an Animal Model for Developing Novel Antimicrobial Agents

Abstract

The demand for novel antibiotics to combat the global spread of multi drug-resistant pathogens continues to grow. Pathogenic bacteria and fungi that cause fatal human infections can also kill silkworms and the infected silkworms can be cured by the same antibiotics used to treat infections in the clinic. As an invertebrate model, silkworm model is characterized by its convenience, low cost, no ethical issues. The presence of conserved immune response and similar pharmacokinetics compared to mammals make silkworm infection model suitable to examine the therapeutic effectiveness of antimicrobial agents. Based on this, we utilized silkworm bacterial infection model to screen the therapeutic effectiveness of various microbial culture broths and successfully identified a therapeutically effective novel antibiotic, lysocin E, which has a novel mode of action of binding to menaquinone, thus leading to membrane damage and bactericidal activity. The similar approach to screen potential antibiotics resulted in the identification of other therapeutically effective novel antibiotics, such as nosokomycin and ASP2397 (VL-2397). In this regard, we propose that the silkworm antibiotic screening model is very effective for identifying novel antibiotics. In this review, we summarize the advantages of the silkworm model and propose that the utilization of silkworm infection model will facilitate the discovery of novel therapeutically effective antimicrobial agents.

Keywords: lysocin E; novel antibiotics; pharmacokinetics; silkworm model; therapeutic activity.

Figure 1

Silkworm and its organs. (A) Manual injection of a sample into the silkworm hemolymph using a 1-ml disposable syringe, and (B) comparison of silkworm organs involved in drug absorption, metabolism, and elimination between silkworms and mammals.

Figure 2

Utilization of silkworms to screen therapeutically active antimicrobial agents.

Figure 3

Lysocins, mode of action, and biosynthesis. (A) Chemical structure of lysocins A–I and (B) schematic representation of membrane damage by lysocin E (C) non-ribosomal peptide synthetases involved in lysocin biosynthesis and amino acids activated by the 12 modules in LesA and LesB.

Figure 4

Chemical structure of the novel antifungal compound ASP2397 (VL-2397). ASP2397, purified based on in-vivo therapeutic effect in silkworm infection model.