Staphylococcus hyicus, considered as a leading pathogen of exudative epidermitis, is a serious threat to humans and animals. The emergency of bacterial resistance to antibiotics, especially in human and animal health fields, leads to an urgent need of exploration of new antimicrobial agents. In this study, NZX, a plectasin-derived peptide, was firstly expressed in Pichia pastoris X-33 and was purified by cation exchange chromatography, followed by detection of its antibacterial activity in vitro and in vivo. The results showed that the total secreted protein concentration in fermentation supernatant was up to 2820 mg/L (29 °C) after 120-h induction in a 5-L fermentor. The yield of NZX reached up to 965 mg/L with a purity of 92.6%. The recombinant expressed NZX had a strong antimicrobial activity, high stability, and low toxicity. The minimal inhibitory concentrations (MICs) of NZX and ceftriaxone (CRO) against Gram-positive bacteria were 0.46 to 0.91 μM and 6.04 to 12.09 μM, respectively. The time-killing curves showed that S. hyicus NCTC10350 was killed completely by 2× and 4 × MIC of NZX within 24 h. NZX also exhibited the intracellular activity against S. hyicus in Hacat cells. After treatment with NZX (10 mg/kg) and CRO (60 mg/kg), the survival rates of mice were 100% and 83.3%, respectively. NZX inhibited the bacterial translocation, downregulated pro-inflammatory cytokines (TNF-α/IL-1β/IL-6), upregulated the anti-inflammatory cytokine (IL-10), and ameliorated multiple-organ injuries (the liver, spleen, lung, and kidney). This study provides evidence that the expressed NZX has the potential to become a powerful candidate as novel antimicrobial agents against S. hyicus infections.

A new high-yielding antimicrobial peptide NZX and its antibacterial activity against Staphylococcus hyicus in vitro/vivo.

Staphylocoagulase (Coa) is a virulence factor of Staphylococcus aureus (S. aureus) that promotes blood coagulation by activating prothrombin to convert fibrinogen to fibrin. Coa plays a crucial role in disease pathogenesis and is a promising target for the treatment of S. aureus infections. Here, we identified that isoquercitrin, a natural flavonol compound, can markedly reduce the activity of Coa at concentrations that have no effect on bacterial growth. Mechanistic studies employing molecular dynamics simulation revealed that isoquercitrin binds to Coa by interacting with Asp-181 and Tyr-188, thereby affecting the binding of Coa to prothrombin. Importantly, in vivo studies showed that isoquercitrin treatment significantly reduced the bacterial burden, pathological damage, and inflammation of lung tissue and improved the percentage of survival of mice infected with S. aureus Newman strain. These data suggest that isoquercitrin is a promising inhibitor of Coa that can be used for the development of therapeutic drugs to combat S. aureus infections.Key Points• Staphylocoagulase plays a key role in the pathogenesis of S. aureus infection.• We identified that isoquercitrin is a direct inhibitor of staphylocoagulase.• Isoquercitrin treatment can significantly attenuate S. aureus virulence in vivo.

Targeting staphylocoagulase with isoquercitrin protects mice from Staphylococcus aureus –induced pneumonia

Staphylococcus hyicus is recognized as a leading pathogen of exudative epidermitis in modern swine industry. Antimicrobial peptides are attractive candidates for development as potential therapeutics to combat the serious threats of the resistance of S. hyicus. In this study, a series of derivatives were designed based on the NZ2114 template with the aim of obtaining peptides with more potent antimicrobial activity through changing net positive charge or hydrophobicity. Among them, a variant designated as NZL was highly expressed in Pichia pastoris (P. pastoris) with total secreted protein of 1505 mg/L in a 5-L fermenter and exhibited enhanced antimicrobial activity relative to parent peptide NZ2114. Additionally, NZL could kill over 99% of S. hyicus NCTC10350 in vitro within 8 h and in Hacat cells. The results of membrane permeabilization assay, morphological observations, peptide localization assay showed that NZL had potent activity against S. hyicus, which maybe kill S. hyicus through action on the cell wall. NZL also showed an effective therapy in a mouse peritonitis model caused by S. hyicus, superior to NZ2114 or ceftriaxone. Overall, these findings can contribute to explore a novel potential candidate against S. hyicus infections.

Design and Pharmacodynamics of Recombinant Fungus Defensin NZL with Improved Activity against Staphylococcus hyicus In Vitro and In Vivo.

There is an urgent need to explore new antimicrobial agents due to the looming threat of bacteria resistance. Bovine lactoferricin (LfcinB), as a multifunctional peptide, has the potential to be a new active drug in the future. In this study, it aims to investigate the effect of fatty acid conjugation on antimicrobial peptide activity and topical therapeutic efficacy in a mouse model infected with Staphylococcus hyicus. Both Lfcin4 and Lfcin5 were conjugated with the unsaturated fatty acid linoleic acid (18-C) at their N-terminus and modified by acylation at the C-terminus. The derived peptides of Lin-Lf4NH2 and Lin-Lf5NH2 showed better antibacterial activity (MICs of 3.27 to 6.64 μM) than their parent peptides (MICs of 1.83 to 59.57 μM). Lin-Lf4NH2 (63.2%, 5 min) and Lin-Lf5NH2 (35.8%, 5 min) could more rapidly penetrate bacterial membrane than Lf4NH2 (2.34%, 5 min) and Lf5NH2 (1.94%, 5 min), which further confirmed by the laser scanning confocal microscopy (LSCM). Electron microscopy observations showed Lin-Lf4NH2 and Lin-Lf5NH2 disrupted S. hyicus cell membranes and led to the leakage of contents. Furthermore, after treatment with Lin-Lf4NH2 and Lin-Lf5NH2, the abscess symptoms of mice were significantly alleviated; the recovery rate of abscesses scope of Lin-Lf4NH2 (73.25%) and Lin-Lf5NH2 (71.71%) were 38.8 and 37.9-fold higher than that of untreated group (1.89%), respectively, and superior to Lf4NH2 (46.87%) and Lf5NH2 (58.75%). They significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and chemokine (MCP-1) in S. hyicus skin lesions. This study provides evidence that conjugation of a fatty acid to antimicrobial peptides can improve the activity and have potential for topical therapeutic of S. hyicus skin infections. KEY POINTS: • Lin-Lfcin4NH2/Lfcin5NH2 showed stronger antimicrobial activity than parent peptides. • Lin-Lfcin4NH2/Lfcin5NH2 had a more effective ability to destroy bacterial membranes. • Lin-Lfcin4NH2/Lfcin5NH2 showed a topically higher efficacy than parent peptides.

Fatty acid modified-antimicrobial peptide analogues with potent antimicrobial activity and topical therapeutic efficacy against Staphylococcus hyicus.

Staphylococcus hyicus is the most common causative agent of exudative epidermitis (EE) in piglets. Staphylococcus hyicus can be grouped into toxigenic and non-toxigenic strains based on its ability to cause EE in pigs. However, the inflammatory response of piglets infected with toxigenic and non-toxigenic S. hyicus has not been elucidated. In this study, we evaluated the serum cytokine profile in piglets inoculated with toxigenic and non-toxigenic S. hyicus strains and recorded the clinical signs in piglets. Fifteen piglets were divided into three groups (n = 5) and inoculated with a toxigenic strain (ZC-4), a non-toxigenic strain (CF-1), and PBS (control), respectively. The changes in serum levels of cytokines (interleukin [IL]-1β, IL-4, IL-6, IL-8, IL-10, IL-12, granulocyte-macrophage colony-stimulating factor, interferon-γ, transforming growth factor-β1, and tumor necrosis factor-α) were evaluated using a cytokine array at 6, 24, 48, and 72 h post inoculation. The results showed that piglets infected with the toxigenic strain exhibited more severe clinical signs and higher mortality than those infected with the non-toxigenic strain. The serum levels of pro-inflammatory cytokine IL-1β were significantly increased in toxigenic-and non-toxigenic-strain-infected piglets compared to those in the control group (p < 0.05), while the anti-inflammatory cytokine IL-10 was significantly up-regulated only in toxigenic group than in control group (p < 0.05). These results indicated that piglets infected with toxigenic and non-toxigenic S. hyicus showed differential infection status and inflammatory responses. Both toxigenic- and non-toxigenic- S. hyicus infection could induce a pro-inflammatory reaction in piglets. In addition, the toxigenic strain induced a strong anti-inflammatory response in piglets as indicated by the increased serum level of IL-10, which may be associated with the severe clinical signs and increased mortality and may be the key cytokine response responsible for pathogenic mechanisms of S. hyicus.

/pdf/comparison-of-host-cytokine-response-in-piglets-infected-32va58zlb0.pdf

Comparison of Host Cytokine Response in Piglets Infected With Toxigenic and Non-toxigenic Staphylococcus hyicus.

Staphylococcus hyicus is one of the opportunistic pathogens that cause infections to animals. Early studies have demonstrated that S. hyicus is the causative agents of exudative epidermitis in pigs, arthritis in horses and chicken, mastitis in cow, and bacteremia, sepsis and multiple organ failure in humans. Here, we report the isolation and identification of a representative S. hyicus isolate, named JLHN15, from a pig farm with a disease characterized by bacteremia, suppurative pneumonia and fibrinous pericarditis. Our results indicate that JLHN15 is a pathogenic coagulase-positive Staphylococcus. To the best knowledge, this is the first report of S. hyicus causing an infection characterized by suppurative pneumonia and sepsis.

A fatal suppurative pneumonia in piglets caused by a pathogenic coagulase-positive strain of Staphylococcus hyicus

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A fatal suppurative pneumonia in piglets caused by a pathogenic coagulase-positive strain of Staphylococcus hyicus