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.
Highlights
It is no exaggeration to say that antibiotics have rewriting the history of public health in the past few decades [1]
The results showed that mice were challenged with LPS for 30 min. treatment of LPS-challenged mice with microcin J25 (MccJ25) significantly reduced the mRNA expression of tumor necrosis factor-a (TNF-a), Toll-like receptor 4 (TLR4), and IL-6 in the jejunum, ileum and spleen and alleviated inflammation and disease damage at these sites
We uncovered that pretreated with MccJ25 effectively protected mice to defense against cocktail clinically source Multidrug resistant (MDR) E. coli strains infection by prolonging the lifespan, increasing body weight, and decreasing diarrhea incidence. These results are line with previous studies that Antimicrobial peptides (AMPs) significantly improved clinical symptoms by regulating immune function and improving gut microbiota composition, thereby inhibiting colonization and translocation of pathogens using infective animal model [32, 38, 39, 77]. Consistent with these previous reports, in this study, we found that MccJ25 harbors a significant improved defense response against the Inflammatory bowel disease caused by pathogenic microorganisms, especially multi-drug resistant bacteria
Summary
It is no exaggeration to say that antibiotics have rewriting the history of public health in the past few decades [1]. In the postantibiotic era, the increase in antibiotic resistance has become one of the most serious health problems worldwide, so the misuse of antibiotics has led to an increasing rate of failure in the treatment of various infectious diseases [2–5]. Bacterial infections in the postantibiotic era, especially multidrugresistant (MDR) strains, are becoming the biggest killers. The problem of bacterial resistance, if not addressed in time, will lead to a return to the preantibiotic era, where life is fragile, a common disease could be fatal, wound, infection and deaths can be induced . To catch more attention to this issue, in the quest for novel alternatives, new strategies are urgently needed to tackle the problem of antibiotic resistance. New types of antibacterial alternatives to antibiotics and strategies urgently need to be identified
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