Biosynthetic Microcin J25 Exerts Strong Antibacterial, Anti-Inflammatory Activities, Low Cytotoxicity Without Increasing Drug-Resistance to Bacteria Target

Abstract

Multidrug resistant (MDR) bacterial infection has emerged, raising concerns about untreatable infections, and posing the highest health risks. Antimicrobial peptides (AMPs) are thought to be the best remedy for this problem. Here, we showed biosynthetic microcin J25 (MccJ25) exhibited excellent bactericidal activity against standard and clinically relevant veterinary MDR strains with high stability, no cytotoxicity, and no increase in drug resistance. Analysis of antimicrobial mechanism possessed by sensitive enterotoxigenic Escherichia coli (ETEC) based on electron microscopy and Sytox Green methods was carried out. Results showed excellent activity against ETEC was due to permeabilizing bacterial membranes and strong affinity. MccJ25 exhibited high endotoxin-neutralizing activity in both in vivo and in vitro environments, and mice exposed to lipopolysaccharide (LPS) showed decreased plasma LPS levels and improved survival after administration of MccJ25. In an LPS-treated mouse septicemia model, MccJ25 treatment significantly alleviated inflammatory responses by inhibiting proinflammatory factor secretion and expression. In a mouse E. coli infection model, administration of MccJ25 effectively improved host defense against clinically source cocktail of multidrug-resistant E. coli strains induced intestinal inflammation and bacteria dissemination. Results of studies on anti-inflammatory mechanisms showed that MccJ25 downregulated nuclear factor kappa B kinase and mitogen-activated protein kinase, thereby reducing the production of toll-like receptor 4, myeloid differentiation factor 88 and decreasing the key proinflammatory cytokines. These findings clarify MccJ25 may be an ideal antibacterial/antiendotoxic drug candidate that has the potential to further guide the development of anti-inflammatory and/or antimicrobial agents in the war against MDR bacterial infection.

Impact of microcin J25 on the porcine microbiome in a continuous culture model

“…Indeed, MccJ25, which is produced by bacteria of the family Enterobacteriaceae and contributes to competition in the gut has a narrow spectrum of antibacterial activity. It is reportedly bactericidal to Gram-negative species including E. coli , Salmonella and Shigella ( Rintoul et al, 2001 ; Yu et al, 2022 ). Highly purified MccJ25 was recently shown to exert efficient bactericidal activity in vitro against clinically relevant veterinary multidrug-resistant strains and to decrease inflammation in a mouse E. coli infection model ( Yu et al, 2022 ).…”

A truncated peptide Spgillcin177–189 derived from mud crab Scylla paramamosain exerting multiple antibacterial activities

“…The thermal activity of Spgillcin 177–189 against S. aureus and P. aeruginosa was evaluated based on a previous report ( Yu et al., 2022 ) with some modifications. Briefly, a logarithmic-growth phase of S. aureus and P. aeruginosa was harvested and diluted to approximately 1 × 10 6 CFU ml -1 .…”

“…In this study, Spgillcin 177-189 maintained its antimicrobial activity and was stable even with changing temperature and salt conditions. A steady-state condition may be a prerequisite for the further application of Spgillcin 177-189 , as it has been reported previously that the AMP Microcin J25 can effectively kill MDR E. coli even during fluctuating pH and temperature (Yu et al, 2022). Cytotoxicity is also a primary drawback to the clinical application of peptide drugs (van der Kraan et al, 2004), also restricting the topical utilization of AMPs.…”

Microcins reveal natural mechanisms of bacterial manipulation to inform therapeutic development

“…Studies demonstrating regulation of microbial communities using purified microcin have emerged only in the last few years, probably due to improvements in the purification process. The majority of these have examined purified MccJ25 treatment [184, 187–191], though one study used purified MccC [185]. With MccJ25, there has been an emphasis on investigating its anti-inflammatory properties and improvements in intestinal barrier function, which are presumably due, at least in part, to effects on the microbial community and/or elimination of specific pathogens [184, 187, 190, 191].…”

“…The majority of these have examined purified MccJ25 treatment [184, 187–191], though one study used purified MccC [185]. With MccJ25, there has been an emphasis on investigating its anti-inflammatory properties and improvements in intestinal barrier function, which are presumably due, at least in part, to effects on the microbial community and/or elimination of specific pathogens [184, 187, 190, 191]. Several of these studies have found increases in the abundance of specific taxonomic groups (e.g.…”