Abstract
Recently, bioactive peptides have attracted attention for their therapeutic applications in the pharmaceutical industry. Among them, antimicrobial peptides are candidates for new antibiotic drugs. Since pseudin-2 (Ps), isolated from the skin of the paradoxical frog Pseudis paradoxa, shows broad-spectrum antibacterial activity with high cytotoxicity, we previously designed Ps-K18 with a Lys substitution for Leu18 in Ps, which showed high antibacterial activity and low toxicity. Here, we examined the potency of Ps-K18, aiming to develop antibiotics derived from bioactive peptides for the treatment of Gram-negative sepsis. We first investigated the antibacterial mechanism of Ps-K18 based on confocal micrographs and field emission scanning electron microscopy, confirming that Ps-K18 targets the bacterial membrane. Anti-inflammatory mechanism of Ps-K18 was investigated by secreted alkaline phosphatase reporter gene assays and RT-PCR, which revealed that Ps-K18 activates innate defense via Toll-like receptor 4-mediated nuclear factor-kappa B signaling pathways. Moreover, we investigated the antiseptic effect of Ps-K18 using a lipopolysaccharide or Escherichia coli K1-induced septic shock mouse model. Ps-K18 significantly reduced bacterial growth and inflammatory responses in the septic shock model. Ps-K18 showed low renal and liver toxicity and attenuated lung damage effectively. This study suggests that Ps-K18 is a potent peptide antibiotic that could be applied therapeutically to Gram-negative sepsis.
Highlights
Occurring bioactive peptides in various organisms are selective and effective cellular signaling molecules that play an important role either directly or indirectly in physiological processes
We demonstrated that Ps-K18 is a potent peptide antibiotic in vitro, with antibacterial activity that effectively relies on interactions with bacterial membranes to induce the death of bacteria, as well as anti-inflammatory effects that inhibit TLR4-mediated NF-κB signaling pathways
Our study showed that Ps-K18 has low toxicity upon Lys substitution at Leu18 in Ps and functions through antibacterial mechanisms to restrict bacterial growth by targeting bacterial membranes and anti-inflammatory mechanism-inhibiting inflammatory reactions by suppressing LPS-induced TLR4 signaling with high specificity in vivo and in vitro
Summary
Occurring bioactive peptides in various organisms are selective and effective cellular signaling molecules that play an important role either directly or indirectly in physiological processes. The peptides released through systems such as food processing or microbial fermentation play physicochemical roles to regulate important processes and exert beneficial effects on body functions [1]. Most peptides bind certain cell surface receptors such as G protein-coupled receptors (GPCRs) or ion channels, causing intracellular effects [2]. They can act as hormones, neurotransmitters, growth factors, ion channel ligands, or anti-infectious agents, and these characteristics have become valuable to treat diseases that could not be cured previously [2,3]. Many peptide drugs approved by the FDA have been supplied to the market and the number of peptide drugs under clinical development is steadily increasing. [2,6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
