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Abstract: Staphylococcus aureus (S. aureus) is one of the most important pathogens in humans and animals, multiply resistant strains are increasingly widespread, new agents are needed for the treatment of S. aureus. Rhein (RH), a natural plant product, has been reported to have potential antimicrobial activity against S. aureus, but the response mechanisms of S. aureus to RH are still poorly understood. RH showed good in vitro antibacterial activity against all 21 tested S. aureus strains in this experiment. We performed commercial Affymetrix GeneChips™ to determine the overall transcriptional response of S. aureus ATCC25923 triggered by the treatment of subinhibitory concentrations of RH at one time point 45min. A total of 88 genes were identified to be differentially regulated by RH. Of these, 28 transporter genes were differentially regulated by RH; RH stress elevated the transcription of genes (srtB and isdABCDEFGI) encoding iron-regulated surface determinants system and genes (nrdIEF and nrdDG) involved in ribonucleotide reductase systems; but RH repressed genes (pflAB, nirBDR, narGH, ldh1, COL-SA0660, COL-SA2363 and COL-SA2386) responsible for anaerobic respiration and fermentation. To our knowledge, this genome-wide transcriptomics approach revealed first insights into the response of S. aureus to RH challenge. [Copyright &y& Elsevier]

The epidermic microbiota plays crucial roles in the pathogenesis of atopic dermatitis (AD), a common inflammatory skin disease. Melatonin (MLT) has been shown to ameliorate skin damage in AD patients, yet the underlying mechanism is unclear. Using 2,4-dinitrofluorobenzene (DNFB) to induce an AD model, MLT intervention was applied for 14 days to observe its pharmaceutical effect. Skin lesions were observed using HE staining, toluidine blue staining and electron microscopy. Dermal proinflammatory factor (IL-4 and IL-13) and intestinal barrier indices (ZO1 and Occludin) were assessed by immunohistochemistry and RT–qPCR, respectively. The dysbiotic microbiota was analyzed using 16S rRNA sequencing. MLT significantly improved skin lesion size; inflammatory status (mast cells, IgE, IL-4, and IL-13); and the imbalance of the epidermal microbiota in AD mice. Notably, Staphylococcus aureus is the key bacterium associated with dysbiosis of the epidermal microbiota and may be involved in the fine modulation of mast cells, IL-4, IL-13 and IgE. Correlation analysis between AD and the gut revealed that intestinal dysbiosis occurred earlier than that of the pathological structure in the gut. Melatonin reverses DNFB-induced skin damage and epidermal dysbiosis, especially in S. aureus. Repeated administration of DNFB activates mast cells and induces the secretion of proinflammatory cytokines in skin tissue, ultimately leading to atopic dermatitis. Melatonin therapy reduces the number of mast cells, inhibits the secretion of IL-4 and IL-13 and the production of IgE, improves dermatitis symptoms and skin microbiota disorders, and reduces the abundance of S. aureus , thus inhibiting AD. [Display omitted] [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (S. aureus) infection is difficult to fight, previous experimental reports have demonstrated thioridazine (TZ) and tetracycline (TC) is an inhibitor of S. aureus efflux pump NorA and autolysin Atl, respectively, here, by means of molecular docking and molecular dynamics simulation, we observed that thioridazine (TZ) and tetracycline (TC) blocked the binding of substrates to NorA and Atl, respectively, and reduced their activities, and our antibacterial susceptibility test and three-dimensional checkerboard method showed that the three-drug combination of antibiotic cloxacillin (CXN), TZ and TC had a synergistic anti-Staphylococcal activity in vitro , and α-Hemolysin tests and scanning electron microscopy showed that the three-drug combination and the subinhibitory concentration of the combination significantly inhibited the secretion of α-hemolysin relative to the number of membrane-derived vesicles produced by S. aureus. Whereas Western blot and pharmacological inhibition assays showed that the three-drug combination significantly inhibited the expression of MAPK/NF-κB/NLRP3 proteins in macrophages induced with S. aureus α-hemolysin. In vivo , the drug combination significantly reduced bacterial colony-forming unit counts in the viscera of a mouse peritonitis model of S. aureus infection, therapy reduced the primary inflammatory pathology and the bacteria-stimulated release of cytokines such as IL-1β and TNF-α, and inhibited the expression of MAPK/NF-κB/NLRP3 proteins in peritoneal macrophages. Thus, the combination of efflux pump inhibitor, autolysis inhibitor and antibiotic, is a novel anti-Staphylococcal and anti-inflammatory strategy who owning good antibacterial activity and significant inhibiting staphylococcal α-hemolysin and inflammation. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) complicated with Staphylococcus aureus (S. aureus) infection lacks effective treatment strategies. In this study, we found that insulin combined with linezolid has potential to deal with the thorny problem. In vitro , our drug sensitivity assay, bacterial growth curve and hemolytic tests showed that a combination of insulin and linezolid exerted good antibacterial and anti-α-hemolysin activity, CCK8 experiment, glucose content and glycogen content determination showed that the combination of insulin and linezolid increased murine macrophage survival rate and reduced the extracellular glucose level of high glucose-treated MH-S cells and intracellular glycogen level, and Western blot showed that the combination inhibited TLR2/MAPKs/NLRP3-related inflammatory pathways in MH-S cells. The results of in vivo experiments showed that the combination therapy stabilized glucose level, remained body weight, ameliorated lung injury including improving pulmonary edema and decreasing lung wet/dry weight ratio, reduced the CFUs and inflammation in the lung tissue in a mouse model of diabetes with S. aureus pneumonia, and inhibited the expression of TLR2, MAPKs and NLRP3 inflammatory pathway. Overall, the combination of insulin and linezolid as autolytic inhibitor exhibited the effects of significant antibacterial and improving glucose level in vitro and in vivo , and also has an anti-inflammation activity via the TLR2/MAPKs/NLRP3 pathway, this paves the way for new treatments for diabetes mellitus complicated with S. aureus infection. [ABSTRACT FROM AUTHOR]

Aim To explore the role of tumor necrosis factor-alpha (TNF-α) on Staphylococcus aureus -induced necroptosis in alveolar epithelial cells. Main methods The A549 alveolar epithelial cell line was pretreated with small interfering RNA (siRNA) against receptor interacting protein-3 (RIP3) and then stimulated by S. aureus , where some cells were pretreated with TNF-α or TNF-α with anti-TNF-α antibody simultaneously. A549 cell death was assessed using lactate dehydrogenase (LDH) leakage and flow cytometry analyses. The protein expressions of RIP1, RIP3, cleaved caspase-1, and cleaved caspase-8 were analyzed by western blot. Key findings S. aureus -induced LDH release was increased significantly by TNF-α. In addition, flow cytometry showed that TNF-α increased A549 cell apoptosis and necrosis in S. aureus -infected cell cultures. Levels of RIP3 and cleaved caspase-1 protein in A549 cells infected with S. aureus increased at 12 h post-infection, as shown by western blot. Significant additional increases in RIP3 expression were observed following the addition of TNF-α. Decreasing RIP3 levels by siRNA significantly suppressed the release of LDH induced by TNF-α and S. aureus . RIP3 siRNA also significantly suppressed A549 cell necrosis induced by S. aureus and TNF-α at 6 and 12 h post-infection as shown by flow cytometry analysis. Significance TNF-α enhances the damage of S. aureus on lung epithelial cells, and its mechanism is associated with RIP3 mediated necroptosis. [ABSTRACT FROM AUTHOR]

The bacterium Staphylococcus aureus is most often recognized as a common cause of food poisoning. S. aureus colonization in humans can cause serious infections, toxinoses and life-threatening diseases. Nisin is a bacteriocin that has been extensively used as a natural preservative in the food industry, but the overall transcriptional response of S. aureus to nisin has not been well characterized. We used whole-genome DNA microarrays of S. aureus to determine the global transcription profile triggered by nisin treatment in S. aureus . In response to nisin treatment, a total of 601 genes were differentially regulated; transcription of 327 genes was up-regulated, and transcription of 274 genes was down-regulated. Various transporter genes showed elevated transcription, including genes involved in capsule polysaccharide (CP) synthesis, cell-wall synthesis, nucleic-acid and nucleotide metabolism as well as genes encoding urease, transport/binding proteins, and lipoproteins. To our knowledge, this transcriptome analysis provides the first insights into the transcriptional response of S. aureus to nisin challenge and enables exploration of the mechanisms of nisin antimicrobial activity toward S. aureus . The findings suggest that nisin regulates multiple desirable targets which could be further explored in the development of new food preservatives to avoid the contamination of S. aureus in food processing and storage. [ABSTRACT FROM AUTHOR]

Nisin has been widely used as a natural preservative in foods including dairy products, but the emergence of the nisin-resistant strains could compromise its use to control food-borne pathogens. It has been reported that coenzyme Q (CoQ) is a powerful antioxidant, but a small number of studies have described the antibacterial activity of CoQ. One of the most abundant forms of CoQ is CoQ10. CoQ0 is chosen for this study, which is the water-soluble homolog of CoQ10. In the present study, the in vitro interaction of nisin and CoQ0 against 15 food-borne isolates of Staphylococcus aureus was assessed using a checkerboard microdilution method. Synergism was observed in strains tested, the FICI values ranging from 0.25 to 0.375. No antagonistic interaction between nisin and CoQ0 occurred. The positive interactions were verified confirmed using the time-killing test and agar diffusion assay. Our discovery of efficacy of combining nisin with CoQ0 might pave the way for a novel solution for spoilage problem in food industry and provide an alternative approach to overcome antimicrobial drug resistance. [ABSTRACT FROM AUTHOR]