bay-11-7082 and Staphylococcal-Infections

The electrophilic potential of vinyl sulfone permits the rapid capture of cysteine-containing proteins under physiological conditions. These cysteine proteinases play vital roles in bacterial survival and pathogenesis of Staphylococcus aureus (S. aureus) and the global health threat methicillin resistant S. aureus (MRSA). Here in, total of 28 vinyl sulfones were synthesized and subjected to susceptibility testing of pathogenic bacteria, including global epidemic MRSA PFGE strain type USA300 (SF8300). Number of antibacterial vinyl sulfone derivatives were discovered. Among these, nitrile-substituted vinyl phenyl sulfones showed potent antibacterial activity. (E)-3-((4-methoxyphenyl)sulfonyl)acrylonitrile exhibited the strongest potency with MIC of 1.875 µg/mL against methicillin susceptible S. aureus and 3.75 µg/mL against MRSA USA300. Based on the structure-activity relationship analysis, the antibacterial activity of these compounds may involve sulfhydryl conjugation. In addition, the nitrile-substituted vinyl phenyl sulfone could also impair host cell adhesion. With their promising antibacterial activities, these vinyl sulfones have potential for S. aureus and MRSA therapeutics.

Topics: Anti-Bacterial Agents; Bacteria; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Nitriles; Staphylococcal Infections; Staphylococcus aureus; Sulfones

The epithelium is an active participant in the host response to infection. We hypothesized that epididymal epithelia play a role in the innate immune responses by sensing the presence of pathogens, expressing and secreting inflammatory cytokines that recruit inflammatory cells in response to invading pathogens. Our results indicated that TNF-alpha and IL-1beta could be secreted by the primary cultured rat epididymal cauda epithelia infected with Staphylococcus aureus. Epididymal epithelial-induced nitric oxide synthase (iNOS) expression was up-regulated after S. aureus infection and nitric oxide (NO) was also found to be produced significantly. NF-kappaB inhibitor BAY11-7082 inhibited TNF-alpha secretion completely and p38 mitogen-activated protein kinases (MAPKs) inhibitor SB203580 decreased TNF-alpha secretion partly, indicating that NF-kappaB and p38 signal pathways were involved in this inflammation response. Toll-like receptor (TLR)-2 and -4 were shown to be expressed in primary cultured rat epididymal epithelia. After infection the level of TLR2 expression was up-regulated rather than TLR4. These results demonstrated that epididymal epithelium have an innate immune response through activation of p38 MAPK and NF-kappaB after TLR2 activation by S. aureus infection.

Topics: Animals; Cell Culture Techniques; Epididymis; Epithelial Cells; Gene Expression Regulation; Genital Diseases, Male; Imidazoles; Immunity, Innate; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Male; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Nitriles; Protein Serine-Threonine Kinases; Pyridines; Rats; Rats, Sprague-Dawley; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; Sulfones; Tumor Necrosis Factor-alpha