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Graphical abstract Abstract Peptide-based vaccines have the potential to overcome the limitations of classical vaccines; however, their use is hampered by a lack of carriers and adjuvants suitable for human use. In this study, an efficient self-adjuvanting peptide vaccine delivery system was developed based on the ionic interactions between cationic trimethyl chitosan (TMC) and a peptide antigen coupled with synthetically defined anionic α-poly-(l -glutamic acid) (PGA). The antigen, possessing a conserved B-cell epitope derived from the group A streptococcus (GAS) pathogen and a universal T-helper epitope, was conjugated to PGA using cycloaddition reaction. The produced anionic conjugate formed nanoparticles (NP-1) through interaction with cationic TMC. These NP-1 induced higher systemic and mucosal antibody titers compared to antigen adjuvanted with standard mucosal adjuvant cholera toxin B subunit or antigen mixed with TMC. The produced serum antibodies were also opsonic against clinically isolated GAS strains. Further, a reduction in bacterial burden was observed in nasal secretions, pharyngeal surface and nasopharyngeal-associated lymphoid tissue of mice immunized with NP-1 in GAS challenge studies. Thus, conjugation of defined-length anionic polymer to peptide antigen as a means of formulating ionic interaction-based nanoparticles with cationic polymer is a promising strategy for peptide antigen delivery. Statement of Significance A self-adjuvanting delivery system is required for peptide vaccines to enhance antigen delivery to immune cells and generate systemic and mucosal immunity. Herein, we developed a novel self-adjuvanting nanoparticulate delivery system for peptide antigens by combining polymer-conjugation and complexation strategies. We conjugated peptide antigen with anionic α-poly-(l -glutamic acid) that in turn, formed nanoparticles with cationic trimethyl chitosan by ionic interactions, without using external crosslinker. On intranasal administration to mice, these nanoparticles induced systemic and mucosal immunity, at low dose. Additionally, nanoparticles provided protection to vaccinated mice against group A streptococcus infection. Thus, this concept should be particularly useful in developing nanoparticles for the delivery of peptide antigens. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that microbiome-host crosstalk regulates intestinal immune activity and predisposition to inflammatory bowel disease (IBD). NF-κB is a master regulator of immune function and a validated target for the treatment of IBD. Here, we identify five Clostridium strains that suppress immune-mediated NF-κB activation in epithelial cell lines, PBMCs, and gut epithelial organoids from healthy human subjects and patients with IBD. Cell-free culture supernatant from Clostridium bolteae AHG0001 strain, but not the reference C. bolteae BAA-613 strain, suppresses inflammatory responses and endoplasmic reticulum stress in gut epithelial organoids derived from Winnie mice. The in vivo responses to Clostridium bolteae AHG0001 and BAA-613 mirror the in vitro activity. Thus, using our in vitro screening of bacteria capable of suppressing NF-κB in the context of IBD and using an ex vivo organoid-based approach, we identify a strain capable of alleviating colitis in a relevant pre-clinical animal model of IBD. [Display omitted] • Select strains of Clostridium from human stool samples can suppress NF-κB activation • The immunomodulatory effect of bacteria can be strain- and media-specific • Inter-patient variation suggests possible development of personalized medicine • In vitro immunosuppression assays using organoids predict in vivo activity The ability of gut bacteria to modulate inflammation remains cryptic. Using anaerobic cultures, Giri et al. identify multiple Firmicutes-affiliated bacteria capable of reducing NF-κB-mediated inflammatory signaling in a strain-dependent manner. Cell-free culture supernatants reduce inflammation in patient-derived organoids and in a pre-clinical model of colitis. [ABSTRACT FROM AUTHOR]

Plant cyanogenesis, the release of cyanide from endogenous cyanide-containing compounds, is an effective herbivore deterrent. This paper characterises cyanogenesis in the Australian tree Eucalyptus polyanthemos Schauer subsp. vestita L. Johnson and K. Hill for the first time. The cyanogenic glucoside prunasin ((R)-mandelonitrile β-D-glucoside) was determined to be the only cyanogenic compound in E. polyanthemos foliage. Two natural populations of E. polyanthemos showed quantitative variation in foliar prunasin concentration, varying from zero (i.e. acyanogenic) to 2.07 mg CN g-1 dry weight in one population and from 0.17 to 1.98 mg CN g-1 dry weight in the other. No significant difference was detected between the populations with respect to the mean prunasin concentration or the degree of variation in foliar prunasin, despite significant differences in foliar nitrogen. Variation between individuals was also observed with respect to the capacity of foliage to catabolise prunasin to form cyanide. Moreover, variation in this capacity generally correlated with the amount of prunasin in the tissue, suggesting genetic linkage between prunasin and β-glucosidase. [Copyright &y& Elsevier]

[Display omitted] Subunit vaccines require an immunostimulant (adjuvant) and/or delivery system to induce immunity. However, currently, available adjuvants are either too dangerous in terms of side effects for human use (experimental adjuvants) or have limited efficacy and applicability. In this study, we examined the capacity of mannose-lipopeptide ligands to enhance the immunogenicity of a vaccine consisting of polyleucine(L 15)-antigen conjugates anchored to liposomes. The clinically tested Group A Streptococcus (GAS) B-cell epitope, J8 , combined with universal T helper PADRE (P) was used as the antigen. Six distinct mannose ligands were incorporated into neutral liposomes carrying L 15 PJ8. While induced antibody titers were relatively low, the ligand carrying mannose, glycine/lysine spacer, and two palmitic acids as liposomal membrane anchoring moieties (ligand 3), induced significantly higher IgG titers than non-mannosylated liposomes. The IgG titers were significantly enhanced when positively charged liposomes were employed. Importantly, the produced antibodies were able to kill GAS bacteria. Unexpectedly, the physical mixture of only ligand 3 and PJ8 produced self-assembled nanorods that induced antibody titers as high as those elicited by the lead liposomal formulation and antigen adjuvanted with the potent, but toxic, complete Freund's adjuvant (CFA). Antibodies produced upon immunization with PJ8 + 3 were even more opsonic than those induced by CFA + PJ8. Importantly, in contrast to CFA, ligand 3 did not induce observable adverse reactions or excessive inflammatory responses. Thus, we demonstrated that a mannose ligand, alone, can serve as an effective vaccine nanoadjuvant. [ABSTRACT FROM AUTHOR]

Quartzite caves located on table-top mountains (tepuis) in the Guyana Shield, are ancient, remote, and pristine subterranean environments where microbes have evolved peculiar metabolic strategies to thrive in silica-rich, slightly acidic and oligotrophic conditions. In this study, we explored the culturable fraction of the microbiota inhabiting the (ortho)quartzite cave systems in Venezuelan tepui (remote table-top mountains) and we investigated their metabolic and enzymatic activities in relation with silica solubilization and extracellular hydrolytic activities as well as the capacity to produce antimicrobial compounds. Eighty microbial strains were isolated with a range of different enzymatic capabilities. More than half of the isolated strains performed at least three enzymatic activities and four bacterial strains displayed antimicrobial activities. The antimicrobial producers Paraburkholderia bryophila CMB_CA002 and Sphingomonas sp. MEM_CA187, were further analyzed by conducting chemotaxonomy, phylogenomics, and phenomics. While the isolate MEM_CA187 represents a novel species of the genus Sphingomonas , for which the name Sphingomonas imawarii sp. nov. is proposed, P. bryophila CMB_CA002 is affiliated with a few strains of the same species that are antimicrobial producers. Chemical analyses demonstrated that CMB_CA002 produces ditropolonyl sulfide that has a broad range of activity and a possibly novel siderophore. Although the antimicrobial compounds produced by MEM_CA187 could not be identified through HPLC-MS analysis due to the absence of reference compounds, it represents the first soil-associated Sphingomonas strain with the capacity to produce antimicrobials. This work provides first insights into the metabolic potential present in quartzite cave systems pointing out that these environments are a novel and still understudied source of microbial strains with biotechnological potential. [Display omitted] • Quartzite caves are rare subterranean environments with still unexplored microbiology. • Eighty isolates were obtained from pristine and remote quartzite caves on tepuis. • More than half of microbial isolates showed enzymatic and/or metabolic activities. • Genome analysis allowed BGCs prediction and phylogenomics of two bioactive strains. • MEM_CA187 isolate belongs to a novel species of Sphingomonas. [ABSTRACT FROM AUTHOR]

Abstract: Chemical investigation of a southern Australian sponge, Pseudoceratina sp., resulted in the isolation of twelve bromotyrosine-derived alkaloids, comprising four new metabolites, aplysamine-7 (1), (−)-purealin B (2), purealin C (3) and purealin D (4); two new spiroisoxazole enantiomers, (−)-purealidin R (5) and (−)-aerophobin-2 (6); five known metabolites (−)-pseudoceratinine A (7), (−)-aeroplysinin-1 (8), aplysamine-2 (9), purpuramine G (10) and purpuramine J (11); and an artifact 12 derived from ethanolysis of 5. Structures for 1–12 were assigned on the basis of detailed spectroscopic analysis. A second southern Australian Pseudoceratina sp. afforded the first recorded account of a racemic bromotyrosine-derived spiroisoxazole, (±)-purealin (13b), together with the known achiral precursor purealidin A (15). A literature review of marine bromotyrosine-derived spiroisoxazoles reaffirmed the published dominance of (+)-spiroisoxazoles, acknowledging several accounts of (−)-spiroisoxazoles, while also revealing a wide range of chiroptical measurements suggestive of variable optical purity. The Pseudoceratina sp. metabolites 1–12, 13b and 15 were assessed for antibiotic properties, with the new metabolites 3 and 13b exhibiting broad spectrum activity against several Gram-positive bacteria. [Copyright &y& Elsevier]

Abstract: Chemical investigation of a southern Australian deep-water marine sponge, Fasciospongia sp., returned the new meroterpene sulfate fascioquinol A (1) together with a series of acid mediated hydrolysis/cyclization products, fascioquinols B (2), C (3) and D (4), and strongylophorine-22 (5). Additional co-metabolites include the new meroterpenes fascioquinol E (6) and fascioquinol F (8), together with the known sponge metabolite geranylgeranyl 1,4-hydroquinone (7). Structures were assigned to 1–8 on the basis of detailed spectroscopic analysis, chemical interconversion, mechanistic and biosynthetic considerations, and literature comparisons. The known 1,4-hydroquinone 7 was identified as the dominant cytotoxic principle in the Fasciospongia sp. extract, with selective inhibitory activity against gastric adenocarcinoma (AGS, IC50 8μM) and neuroblastoma (SH-SY5Y, IC50 4μM) cell lines. By contrast, while the fascioquinols displayed little or no inhibitory activity towards human cell lines, 1 and 2 displayed promising Gram-positive selective antibacterial activity towards Staphylococcus aureus (IC50 0.9–2.5μM) and Bacillus subtilis (IC50 0.3–7.0μM). [Copyright &y& Elsevier]

Abstract: A cyanogenic glycoside – 6′-O-galloylsambunigrin – has been isolated from the foliage of the Australian tropical rainforest tree species Elaeocarpus sericopetalus F. Muell. (Elaeocarpaceae). This is the first formal characterisation of a cyanogenic constituent in the Elaeocarpaceae family, and only the second in the order Malvales. 6′-O-galloylsambunigrin was identified as the principal glycoside, accounting for 91% of total cyanogen in a leaf methanol extract. Preliminary analyses indicated that the remaining cyanogen content may comprise small quantities of sambunigrin, as well as di- and tri-gallates of sambunigrin. E. sericopetalus was found to have foliar concentrations of cyanogenic glycosides among the highest reported for tree leaves, up to 5.2mgCNg−1 dry wt. [Copyright &y& Elsevier]

• Synthesis of echinosulfone A. • Structure revision of the marine natural product echinosulfone A. • Structure revision of the marine natural product echinosulfonic acids A–D. A short Friedel-Crafts mediated total synthesis has informed structure revision of the rare marine sponge natural product echinosulfone A (1a) and the biosynthetically related echinosulfonic acids A–D (2a – 5a). [ABSTRACT FROM AUTHOR]

Synthetic peptide vaccines based on epitopes derived from the conserved region of M-protein are proving to be a realistic option for protection against group A streptococcus (GAS). However, peptide epitopes alone are poorly immunogenic due to lack of pathogen-associated structural patterns. Therefore, we developed a GAS peptide vaccine based on combined lipidic TLR 2 agonist and self-adjuvanting polymers. We synthesized three α-poly- l -glutamic acid (PGA) conjugated lipopeptides composed of 2-amino- d,l -hexadecanoic acid, GAS B-cell peptide epitope J8 (QAEDKVKQSREAKKQVEKALKQLEDKVQ) and universal T-helper epitope PADRE (AKFVAAWTLKAAA) in different spatial arrangements. The anionic lipopeptide conjugates formed nanoparticles via ionic-complexation with a cationic polymer, trimethyl chitosan (TMC). We demonstrated that the spatial arrangement of vaccine components has a significant influence on peptide conformation and particle formation and, as such, contributes to the differential efficacy and opsonin-mediated killing potential of nanovaccines. Nanoparticles carrying branched helical lipopeptide with T-helper epitope on free N-termini (NP3) stimulated the most potent humoral immune responses. Lipopeptides without TMC (LP1-LP3) and TMC nanoparticles of peptide alone (without lipid) NP (P1) were poor inducers of antibody production, indicating that both TMC and lipid are required to induce a strong opsonic immune response. Image 1 • Spatial arrangement of vaccine components influenced its conformational properties. • The conformational change resulted in different nanoparticle morphology. • Nanovaccines carrying branched helical lipopeptides stimulated potent immune response. • Both cationic polymer and lipid were necessary to induce a strong opsonic response. [ABSTRACT FROM AUTHOR]

Short peptides derived from virulent pathogen proteins are promising antigens for the development of vaccines against infectious diseases. However, in order to mimic the danger signals associated with natural infection and stimulate an adaptive immune response, peptide antigens must be co-delivered with immune adjuvants. In this study, a group A streptococcus (GAS) M-protein derived B-cell epitope: J8, and universal T-helper epitope P25 containing peptides, were chemically coupled with different anionic amino acid-based polymers. The poly(anionic amino acid)-peptide antigen conjugates were mixed with trimethyl chitosan (TMC) to produce self-adjuvanting nanoparticulate vaccine candidates. TMC from two different sources were used to analyse their effect on immunogenicity. The nanoparticles produced from a peptide modified with 10 residues of polyglutamic acid and fungal TMC (NP5) stimulated production of the highest levels of serum antibodies in outbred mice. These antibodies were opsonic against all clinical GAS isolates tested. [ABSTRACT FROM AUTHOR]

Abstract This study describes an investigation into polybromocatechol conjugates isolated from a marine red alga, Symphyocladia latiuscula (Harvey) Yamada, collected from coastal waters off Qingdao, China. We report on the isolation and characterisation of eight undescribed aconitic acid conjugates, symphyocladins R-X, including a likely solvolysis artifact of symphyocladin S, and an undescribed furanoyl conjugate, symphyocladin Y. Structure elucidation was achieved by detailed spectroscopic analysis. A plausible biosynthetic pathway linking all these co-metabolites through a cascade of quinone methide additions is proposed. Graphical abstract Seven aconitic acid conjugates, symphyocladins R-X, and the furanoyl conjugate, symphyocladin Y, were isolated from a Chinese marine red alga, Symphyocladia latiuscula. Image 1 Highlights • Marine red alga Symphyocladia latiuscula produced 9 previously undescribed polybromocatechol conjugates. • Structure elucidations were achieved by detailed spectroscopic analysis (2D NMR). • A plausible biosynthetic pathway linking these compounds through a cascade of quinone methide is proposed. [ABSTRACT FROM AUTHOR]

Oncogenic RAS proteins are commonly expressed in human cancer. To be functional, RAS proteins must undergo posttranslational modification and localize to the plasma membrane (PM). Therefore, compounds that prevent RAS PM targeting have potential as putative RAS inhibitors. Here we examine the mechanism of action of oxanthroquinone G01 (G01), a recently described inhibitor of KRASPMlocalization. We show that G01 mislocalizes HRAS and KRAS from thePMwith similar potency and disrupts the spatial organization of RAS proteins remaining on the PM. G01 also inhibited recycling of epidermal growth factor receptor and transferrin receptor, but did not impair internalization of cholera toxin, indicating suppression of recycling endosome function. In searching for the mechanism of impaired endosomal recycling we observed that G01 also enhanced cellular sphingomyelin (SM) and ceramide levels and disrupted the localization of several lipid and cholesterol reporters, suggesting that the G01 molecular target may involve SM metabolism. Indeed, G01 exhibited potent synergy with other compounds that target SM metabolism in KRAS localization assays. Furthermore, G01 significantly abrogated RASRAF- MAPK signaling in Madin-Darby canine kidney (MDCK) cells expressing constitutively activated, oncogenic mutant RASG12V. G01 also inhibited the proliferation of RAS-less mouse embryo fibroblasts expressing oncogenic mutant KRASG12V or KRASG12D but not RAS-less mouse embryo fibroblasts expressing oncogenic mutant BRAFV600E. Consistent with these effects, G01 selectively inhibited the proliferation of KRAS-transformed pancreatic, colon, and endometrial cancer cells. Taken together, these results suggest that G01 should undergo further evaluation as a potential anti-RAS therapeutic. [ABSTRACT FROM AUTHOR]

Chemical investigation of two Irciniidae sponges collected by hand (SCUBA) from Australian near shore waters, afforded six new examples of a rare class of sesterterpene lactam; ircinialactams B ( 1 ), G ( 2 ), H ( 5 ), and I ( 6 ), and 8-hydroxyircinialactams C ( 3 ) and G ( 4 ); together with the new biosynthetically related lactone, ircinialactone A ( 7 ). Also isolated were seven biosynthetically related known Irciniidae metabolites; ircinialactams A ( 8 ) and C ( 9 ), (7 E ,12 E ,20 Z ,18 S )-variabilin ( 10 ), (7 Z ,12 Z ,20 Z ,18 S )-variabilin ( 11 ), (7 E ,12 Z ,20 Z ,18 S )-variabilin ( 12 ), (7 Z ,12 E ,20 Z ,18 S )-variabilin ( 13 ) and irciniafuran A ( 14 ). The structure elucidation of 1 – 14 was achieved by detailed spectroscopic analysis, and consideration of a plausible biosynthetic relationship linking Irciniidae sesterterpene β-furans, lactams and lactones. [ABSTRACT FROM AUTHOR]

Chemical and cultivation profiling of an Australian Mugil mullet gastrointestinal tract (GIT) derived fungus, Metarhizium sp. CMB-F624, prompted investigation of a scaled up rice grain cultivation leading to the discovery of three new PKS-NRPS macrolides, metarhizides A-C (1 – 3) featuring an unusual tautomerically labile α-methyl-β-keto-macrolactone, together with two new aromatic glycosides, metarhizosides A and B (4 – 5). Structures were assigned to 1 – 5 on the basis of detailed spectroscopic and chemical analysis, and biosynthetic considerations. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Chemical analysis of a specimen of the sponge Ianthella cf. flabelliformis returned two new sesquiterpene glycinyl lactams, ianthellalactams A (1) and B (2), the known sponge sesquiterpene dictyodendrillin (3) and its ethanolysis artifact ethyl dictyodendrillin (4), and five known sponge indole alkaloids, aplysinopsin (5), 8E-3′-deimino-3′-oxoaplysinopsin (6), 8Z-3′-deimino-3′-oxoaplysinopsin (7), dihydroaplysinopsin (8) and tubastrindole B (9). The equilibrated mixture 6/7 exhibited glycine-gated chloride channel receptor (GlyR) antagonist activity with a bias towards α3 over α1 GlyR, while tubastrindole B (9) exhibited a bias towards α1 over α3 GlyR. At low- to sub-micromolar concentrations, 9 was also a selective potentiator of α1 GlyR, with no effect on α3 GlyR—a pharmacology that could prove useful in the treatment of movement disorders such as spasticity and hyperekplexia. Our investigations into the GlyR modulatory properties of 1–9 were further supported by the synthesis of a number of structurally related indole alkaloids. [Copyright &y& Elsevier]

Abstract: High intrinsic or acquired expression of membrane spanning, adenosine triphosphate binding cassette (ABC) transporter proteins, such as P-glycoprotein (P-gp), in cancers represents a major impediment to chemotherapy, with accelerated drug efflux leading to multi-drug resistance (MDR). Although ABC transporter inhibitors offer the prospect of reversing the MDR phenotype, no inhibitors have advanced to the clinic. We employed a range of intracellular fluorescence and radio-ligand accumulation and efflux assays, together with cytotoxicity and MDR reversal assays, as well as flow cytometry, fluorescence microscopy and radioimmunoprecipitation, to discover and evaluate new P-gp inhibitors from a unique library of southern Australian and Antarctic marine natural products. This study successfully characterized two rare bromoditerpenes, parguerenes I and II, sourced from a southern Australian collection of the red alga Laurencia filiformis, as P-gp inhibitors. We determined that the parguerenes were non-cytotoxic, dose-dependent inhibitors of P-gp mediated drug efflux, that modify the extracellular antibody binding epitope of P-gp in a manner that differs markedly from that of the known inhibitors verapamil and cyclosporine A. We confirmed that parguerenes were capable of reversing P-gp mediated vinblastine, doxorubicin and paclitaxel MDR, that inhibitory properties span both P-gp and multidrug resistant protein 1 (MRP1), but do not extend to breast cancer resistance protein (BCRP), and that parguerene II is superior (more potent) to verapamil. Our investigations validate the proposition that marine natural products can deliver new ABC transporter inhibitor scaffolds, with structure characteristics fundamentally different from existing inhibitor classes. [Copyright &y& Elsevier]

Abstract: A Nocardiopsis sp. (CMB-M0232) recovered from marine sediment collected off the coast of South Molle Island, Queensland, Australia, yielded two new examples of rare prolinyl-macrolactam polyketides, nocardiopsins C (1) and D (2), a new highly substituted α-pyrone polyketide, nocardiopyrone A (3), and the previously reported macrolide polyketides nocardiopsins A (4) and B (5). Structures were assigned on the basis of detailed spectroscopic analysis, degradation, and chemical derivatization. PCR amplification of CMB-M0232 genomic DNA revealed the presence of type I and type II polyketide synthase and non-ribosomal peptide synthase domains. [Copyright &y& Elsevier]

Oncogenic mutant Ras is frequently expressed in human cancers, but no anti-Ras drugs have been developed. Since membrane association is essential for Ras biological activity, we developed a high content assay for inhibitors of Ras plasma membrane localization. We discovered that staurosporine and analogs potently inhibit Ras plasma membrane binding by blocking endosomal recycling of phosphatidylserine, resulting in redistribution of phosphatidylserine from plasma membrane to endomembrane. Staurosporines are more active against K-Ras than H-Ras. K-Ras is displaced to endosomes and undergoes proteasomal-independent degradation, whereas H-Ras redistributes to the Golgi and is not degraded. K-Ras nanoclustering on the plasma membrane is also inhibited. Ras mislocalization does not correlate with protein kinase C inhibition or induction of apoptosis. Staurosporines selectively abrogate K-Ras signaling and proliferation of K-Ras-transformed cells. These results identify staurosporines as novel inhibitors of phosphatidylserine trafficking, yield new insights into the role of phosphatidylserine and electrostatics in Ras plasma membrane targeting, and validate a new target for anti-Ras therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: Biological screening of a deep-water Great Australian Bight marine sponge, Axinella sp., detected inhibition against the neurodegenerative disease kinase targets CDK5/p25, CK1δ, and GSK3β, as well as significant levels of antibacterial activity. Chemical fractionation returned 18 secondary metabolites identified by detailed spectroscopic analysis as three new bromopyrrolo-2-aminoimidazoles, 14-O-sulfate massadine (1), 14-O-methyl massadine (2), and 3-O-methyl massadine chloride (3), together with the known metabolites massadine chloride (4), massadine (5), stylissadine B (6), axinellamines A–C (7–9), hymenin (10), stevensine (also known as odiline) (11), tauroacidin A (12), hymenidin (13), taurodispacamide A (14), oroidin (15), debromohymenialdisine (16), hymenialdisine (17), and aldisin (18). Armed with this focused natural product chemical diversity library, we re-established that 16 and 17 were nM kinase inhibitors, and determined that 3, 6, and 12–15 were sub μM antibacterials. [Copyright &y& Elsevier]

Abstract: Chemical analysis of a Chinese collection of the marine red alga Symphyocladia latiuscula yielded five unprecedented bromophenol–aconitic acid adducts, symphyocladins A–E, together with a new example of a bromophenol–pyroglutamic acid adduct, symphyocladin F, a new example of a bromophenol–urea adduct, symphyocladin G, and the known methyl ester of cis-aconitic acid. The structures were assigned on the basis of detailed spectroscopic analysis, and were consistent with a plausible biosynthetic pathway linking these bromophenol natural products with a putative quinone methide intermediate. Symphyocladins A/B and C/D were isolated as inseparable 1:1 mixtures of E/Z isomers. A plausible mechanism for their facile equilibration during handling and storage is presented. The bromophenol–urea exhibits antifungal activity (MIC 10μg/mL) against Candida albicans. [Copyright &y& Elsevier]

Abstract: Screening an extract library of >2500 southern Australian and Antarctic marine invertebrates and algae for modulators of glycine receptor (GlyR) chloride channels identified three Irciniidae sponges that yielded new examples of a rare class of glycinyl lactam sesterterpene, ircinialactam A, 8-hydroxyircinialactam A, 8-hydroxyircinialactam B, ircinialactam C, ent-ircinialactam C and ircinialactam D. Structure–activity relationship (SAR) investigations revealed a new pharmacophore with potent and subunit selective modulatory properties against α1 and α3 GlyR isoforms. Such GlyR modulators have potential application as pharmacological tools, and as leads for the development of GlyR targeting therapeutics to treat chronic inflammatory pain, epilepsy, spasticity and hyperekplexia. [Copyright &y& Elsevier]

[Display omitted] We recently reported that polyethylenimine (PEI; molecular weight of 600 Da) acted as a vaccine adjuvant for liposomal group A Streptococcus (GAS) vaccines, eliciting immune responses in vivo with IgG antibodies giving opsonic activity against five Australian GAS clinical isolates. However, to date, no investigation comparing the structure–activity relationship between the molecular weight of PEI and its adjuvanting activity in vaccine development has been performed. We hypothesized that the molecular weight and quantity of PEI in a liposomal vaccine will impact its adjuvanting properties. In this study, we successfully formulated liposomes containing different molecular weights of PEI (600, 1800, 10k and 25k Da) and equivalents of PEI (0.5, 1 and 2) of branched PEI. Outbred mice were administrated the vaccine formulations intranasally, and the mice that received a high ratio of PEI 600 reported a stronger immune response than the mice that received a lower ratio of PEI 600. Interestingly, mice that received the same quantity of PEI 600, PEI 10k and PEI 25k showed similar immune responses in vivo and in vitro. This comparative study highlights the ratio of PEI present in the liposome vaccines impacts adjuvanting activity, however, PEI molecular weight did not significantly enhance its adjuvanting properties. We also report that the stability of PEI liposomes is critical for vaccines to elicit the desired immune response. [ABSTRACT FROM AUTHOR]

Chemical fractionation of the southern Australian marine sponge Phoriospongia sp. (CMB-03107) yielded phorioadenine A ( 1 ) as a nematocidal agent and the first reported example of a 6- N -acyladenine natural product. The structure of 1 was confirmed by spectroscopic analysis and the chemical synthesis of racemic ( 1a ) and enantiomeric ( 1b ) analogues. HPLC–ESIMS analysis of the crude sponge extract with comparisons to the synthetic 6- N -acyladenosine 2a provided evidence that the biosynthetically related adenosine, phorioadenosine A ( 2 ), was present as a trace co-metabolite. The rare starfish metabolite asterubine ( 3 ) was also isolated as a co-metabolite, and its structure confirmed by spectroscopic analysis and chemical synthesis. Biological investigations confirmed that natural products 1 – 3 and synthetic analogues 1a – e and 2a were not cytotoxic to multiple mammalian cancer cell lines, or Gram-positive or -negative bacteria. Nematocidal activity (inhibition of larval development of Haemonchus contortus ) detected in the Phoriospongia sp. extract was attributed to 1 (LD 99 31 μg/mL), with preliminary structure–activity relationship investigations confirming the importance of the N -acyl side chain. [ABSTRACT FROM AUTHOR]

Abstract: Chemical analysis of an East China Sea marine-derived fungus, Aspergillus sydowii (MF357) returned three new tris-pyrogallol ethers, sydowiols A–C (1–3), and two known bis-pyrogallol ethers, violaceols I (4) and II (5). Structures were assigned on the basis of detailed spectroscopic analysis and by consideration of symmetry. Sydowiols A (1) and C (3) were responsible for the inhibitory activity detected in the crude fungal extract against Mycobacterium tuberculosis protein tyrosine phosphatase A (PtpA). [Copyright &y& Elsevier]

In order to improve the immunogenicity of peptide-based vaccines against group A Streptococcus (GAS), lipid moieties (C16 lipoamino acid and cholic acid) were conjugated with peptide antigen (P25-J8) and further modified with α-poly(glutamic acid) (α-PGA). Thus, positively charged lipopeptide vaccine candidates LCP-1 (P25-K(J8)-SS-C16-C16) and LCP-2 (P25-K(J8)-SS-K(cholic acid)) were synthesized. Negatively charged LCP-3 (P25-K(PGA-J8)-SS-K(cholic acid)) was also produced by attaching α-PGA to the J8 N -terminus of LCP-2. Polyelectrolyte complex (PEC) nanoparticles were formulated with heparin and/or trimethyl chitosan (TMC) for delivery of the lipopeptide vaccine candidates. The ability of the antigen-loaded nanoparticles to induce humoral immune responses was examined in outbred female Swiss mice following intranasal immunization. The antibodies produced were opsonic against all clinical GAS isolates tested. [ABSTRACT FROM AUTHOR]

Abstract: Chemical analysis of a marine-derived Streptomyces sp. (CMB-M0392) isolated from sediment collected off Heron Island, Queensland, Australia, yielded a new benzothiazine ansamycin, heronamycin A. The absolute stereostructure of heronamycin A was determined by detailed spectroscopic analysis and X-ray crystallography. Heronamycin A exhibited modest antimicrobial activity against Bacillus subtilis strains ATCC 6051 and 6633 (IC50 =18 and 14μM, respectively). [Copyright &y& Elsevier]

Abstract: Chemical investigations into samples of Hunteria umbellata (K. Schum) collected in Osun State, Nigeria, led to the discovery of a new indole alkaloid, ikirydinium A, featuring an unprecedented 3-alkylpyridinium-indole-2-carboxylate scaffold. Ikirydinium A was found to exhibit antimicrobial activity (IC50 0.6μM) against Bacillus subtilis ATCC 6051. The involvement of a common intermediate in the biosynthesis of ikirydinium A and vinblastine is hypothesized. [Copyright &y& Elsevier]

Abstract: The cane toad is an invasive pest that is rapidly colonising northern Australia. The cane toad parotoid gland secretes cardiotoxic steroids (bufadienolides) that are poisoning native predator species. This study reveals bufadienolide diversity within the secretions of Australian cane toads is different to cane toads from overseas, being far more structurally diverse than previously assumed. It is proposed that this variation is mediated by in situ bacterial biotransformation. [Copyright &y& Elsevier]

• Miniaturized microtitre plate cultivation accesses silent fungal metabolism. • A wasp-derived fungus yields the first sulfated p-terphenyl. • Sulfated p-terpenyls are acid labile and prone to hydrolysis on handling. Chemical analysis of a jasmine rice cultivation of an Australian mud dauber wasp-associated fungus, Talaromyces sp. CMB-W045, led to the discovery of a new p -terphenyl, talarophenol sulfate (1). The structure elucidation of 1 was achieved by detailed spectroscopic analysis supported by acid hydrolysis to the p -hydroquinone talarophenol (2), and subsequent in situ air oxidation to trace amounts of the p -quinone talaroquinone (3). The same jasmine rice cultivation also yielded the new talarophilones A (4) and B (5), and known (+)-mitorubrin (6) and pochonin D (7), with structures assigned by detailed spectroscopic analysis. Neither 1 or 4 – 7 exhibited growth inhibitory properties against a panel of human cell lines, or bacterial or fungal pathogens, although 1 did exhibit selective antibacterial activity against Streptococcus pyogenes ATCC 12344 (IC 50 10 µM). [ABSTRACT FROM AUTHOR]

Herein, we describe the isolation of rare alkaloids, haenamindole and citreoindole, from a South China Sea deep-sea fungus, Penicillium citrinum (MF006), and their structure revision based on detailed spectroscopic and C 3 Marfey’s analysis. [ABSTRACT FROM AUTHOR]