Abstract
Aeromonas veronii is one of the main pathogens causing various diseases in humans and animals. It is currently difficult to eradicate drug-resistant A. veronii due to the biofilm formation by conventional antibiotic treatments. In this study, a marine peptide-N6NH2 and its analogs were generated by introducing Orn or replacing with D-amino acids, Val and Pro; their enzymic stability and antibacterial/antibiofilm ability against multi-drug resistant (MDR) A. veronii ACCC61732 were detected in vitro and in vivo, respectively. The results showed that DN6NH2 more rapidly killed A. veronii ACCC61732 and had higher stability in trypsin, simulated gastric/intestinal fluid, proteinase K, and mouse serum than the parent peptide-N6NH2. DN6NH2 and other analogs significantly improved the ability of N6NH2 to penetrate the outer membrane of A. veronii ACCC61732. DN6NH2, N6PNH2 and V112N6NH2 protected mice from catheter-associated biofilm infection with MDR A. veronii ACCC61732, superior to N6NH2 and CIP. DN6NH2 had more potent efficacy at a dose of 5 μmol/kg (100% survival) in a mouse peritonitis model than other analogs (50–66.67%) and CIP (83.33%), and it inhibited the bacterial translocation, downregulated pro-inflammatory cytokines, upregulated the anti-inflammatory cytokine, and ameliorated multiple-organ injuries (including the liver, spleen, lung, and kidney). These data suggest that the analogs of N6NH2 may be a candidate for novel antimicrobial and antibiofilm agents against MDR A. veronii infections.
Highlights
Aeromonas veronii is an emerging aquatic pathogen that can cause diarrhea, wound infections, and hemorrhagic septicemia in humans and animals, including aquatic animals with 40–60% cumulative mortality [1,2]
To develop marine peptides with high stability, low toxicity, and high efficacy, four new analogs of N6NH2 were designed based on the following criteria: (a) keeping the structural features (β-sheet) that are crucial for effective antibacterial activity of N6NH2; (b) changing net charge and hydrophobicity; and (c) replacing residues with natural amino acids (Pro and Val) and non-natural ones (D-enantiomers and Orn)
The overall efficacy of peptides at five days was superior to that at 24 h (Figure S12). These results indicate that DN6NH2 and N6NH2 improve the tissue damage or injury in mice induced by A. veronii ACCC61732
Summary
Aeromonas veronii is an emerging aquatic pathogen that can cause diarrhea, wound infections, and hemorrhagic septicemia in humans and animals, including aquatic animals with 40–60% cumulative mortality [1,2]. It has been reported that A. veronii can infect freshwater fish [3,4], amphibians [5], and mammals [6], resulting in serious economic losses to the aquaculture industry and threatening food safety. People can infect through contacting with A. veronii-contaminated surfaces, such as contaminated livestock and poultry meat and seafood, resulting in gastroenteritis [7], wound infections [8], and other diseases in the elderly and children with low immunity [9]. There is an urgent and growing need for the development of alternative antimicrobial agents with superior properties and less toxicity for the prevention and treatment of A. veronii infections
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