Nanolobatone A, An Unprecedented Diterpenoid and Related New Casbanoids from the Hainan Soft Coral Sinularia nanolobata.

Nanolobatone A, featuring an unprecedented tricyclo[10.3.0.01,2 ]pentadecane carbon skeleton, along with four new polyoxygenated and four unusual endoperoxide-bridged casbane-type diterpenoids were isolated from the Hainan soft coral Sinularia nanolobata. The structures of the new compounds were established by extensive spectroscopic analysis, X-ray diffraction analysis, and time-dependent density functional theory/electronic circular dichroism calculations. A plausible biosynthetic pathway of new isolates was proposed. Bioassays revealed that nanolobatone A showed weak antibacterial activity against the Gram-positive bacteria Streptococcus pyogenes.

Cytotoxic and Antibacterial Isomalabaricane Terpenoids from the Sponge Rhabdastrella globostellata.

Nine new isomalabaricane terpenoids (1-9) were isolated from the sponge Rhabdastrella globostellata of Ximao Island, together with 13 known ones (10-22). The structures were established by spectroscopic data interpretation and chemical calculations, as well as by comparison with spectroscopic data of known compounds. Notably, of the new isolates, hainanstelletin A (5) is the first representative of a nitrogenous isomalabaricane. The isolated compounds were evaluated against several cancer cell lines and two bacterial pathogens. In addition, moderate to strong antibacterial activities against Streptococcus pyogenes were also detected among geometric isomers 1, 2, and 10-12, with minimum inhibitory concentrations of 0.1-1.8 µg/mL.

Xishaeleganins A-D, Sesquiterpenoid Hydroquinones from Xisha Marine Sponge Dactylospongia elegans.

Four new sesquiterpene hydroquinones, xishaeleganins A-D (6-9), along with eleven known related ones (12 and 14-23) were isolated from the Xisha marine sponge Dactylospongia elegans (family Thorectida). Their structures were determined by extensive spectroscopic analysis, ECD calculations, and by comparison with the spectral data reported in the literature. Compounds 7, 15, 20, and 21 showed significant antibacterial activity against Staphylococcus aureus, with minimum inhibitory concentration values of 1.5, 2.9, 5.6, and 5.6 µg/mL, which are comparable with those obtained for the positive control vancomycin (MIC: 1.0 µg/mL).

Sinulasterols D-G, four new antibacterial steroids from the South China sea soft coral Sinularia depressa.

Four new steroids, namely sinulasterols D-G (1-4), along with seven known related ones 5-11, were isolated from the Xisha soft coral Sinularia depressa. The structures of the new compounds were elucidated by a combination of extensive spectroscopic analyses, chemical conversion method, and comparison of the NMR data with those of known analogues. In in vitro bioassays, compounds 1-3 showed significant antibacterial activities against gram-positive bacteria Enterococcus faecium with minimum inhibitory concentration (MIC) values of 62.5, 125, and 125 µM, respectively, comparable with that of vancomycin (MIC: >44.2 µM).

Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO.

Phenol-soluble modulins (PSMs) and Staphylococcal protein A (SpA) are key virulence determinants for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), an important human pathogen that causes a wide range of diseases. Here, using chemical and genetic approaches, we show that inhibition of TarO, the first enzyme in the wall teichoic acid (WTA) biosynthetic pathway, decreases the expression of genes encoding PSMs and SpA in the prototypical CA-MRSA strain USA300 LAC. Mechanistically, these effects are linked to the activation of VraRS two-component system that directly represses the expression of accessory gene regulator (agr) locus and spa. The activation of VraRS was due in part to the loss of the functional integrity of penicillin-binding protein 2 (PBP2) in a PBP2a-dependent manner. TarO inhibition can also activate VraRS in a manner independent of PBP2a. We provide multiple lines of evidence that accumulation of lipid-linked peptidoglycan precursors is a trigger for the activation of VraRS. In sum, our results reveal that WTA biosynthesis plays an important role in the regulation of virulence gene expression in CA-MRSA, underlining TarO as an attractive target for anti-virulence therapy. Our data also suggest that acquisition of PBP2a-encoding mecA gene can impart an additional regulatory layer for the modulation of key signaling pathways in S. aureus.