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.

Structural analysis of an innate immunostimulant from broccoli, <i>Brassica oleracea</i> var. <i>italica </i>

“…RH2180-5, using a silkworm model of infection (3). Injection of yeast β-glucans and bacterial peptidoglycans into the silkworm Bombyx mori induces maturation of the insect cytokine paralytic peptide, which results in muscle contraction of the larvae (4,5).…”

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

“…Furthermore, the vinylsulfonamide 86, which was designed as mimic of O-succinylbenzoate-CoA ester was reported to efficiently inhibit MenE at low nanomolar concentrations (Lu et al 2012). Recently, the novel natural cyclodepsipeptide lysocin E 87 (Scheme 28) was reported to target the redox metabolism in bacteria by directly binding to menaquinone (Hamamoto et al 2014). Since the biosynthesis of menaquinone is a multi-enzymatic pathway as described above and the role of menaquinone is crucial for viability of bacteria, menaquinone seems to be a much smarter choice for an antibacterial target than the individual enzymes of the biosynthesis, even more when considering that an alternative biosynthetic pathway for menaquinones starting from futalosine exists in several Gram-positive bacteria.…”

Therapeutic effects of three trichothecenes in the silkworm infection assay with <i>Candida albicans </i>

“…In this assay, candidate compounds or test samples are injected into pathogenic microorganism-infected silkworm larvae and the survival rate over a few days is then evaluated. In a silkworm infection model with methicillin-resistant Staphylococcus aureus (MRSA), nosokomycins (2)(3)(4), and lysocins in bacterial culture broths were identified as effective in vivo anti-MRSA antibiotics (1).…”

“…To overcome these issues, an in vivo-mimic infection assay using the silkworm has been introduced to screening at the early stage and is expected to be a relevant strategy for the discovery of therapeutically effective candidates (1). In this assay, candidate compounds or test samples are injected into pathogenic microorganism-infected silkworm larvae and the survival rate over a few days is then evaluated.…”