ORCID Profile
0000-0002-5308-5314
Current Organisation
Macquarie University
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Biochemistry and Cell Biology | Proteomics and Intermolecular Interactions (excl. Medical Proteomics) | Biologically Active Molecules | Organic Chemistry not elsewhere classified | Synthetic Biology | Natural Products Chemistry | Medicinal and Biomolecular Chemistry | Animal Protection (Pests and Pathogens) | Molecular Targets | Industrial Microbiology (incl. Biofeedstocks)
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences | Infectious Diseases | Crop Protection Chemicals | Human Pharmaceutical Treatments (e.g. Antibiotics) | Veterinary Pharmaceutical Treatments (e.g. Antibiotics) | Animal Protection Chemicals |
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D2NP00070A
Abstract: Fungi are prolific producers of piperazine alkaloids, with more than 90 ex les isolated to date. This review summarises the current knowledge of the discovery, classification, bioactivity and biosynthesis of fungal piperazines up to July of 2022.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 12-2012
Publisher: MDPI AG
Date: 04-12-2019
DOI: 10.3390/MD17120683
Abstract: Chemical investigation of the secondary metabolites of a rare New Zealand deep-sea sponge, Lamellomorpha strongylata, resulted in the isolation of twenty-one indole alkaloids, including two new bisindoles—(Z)-coscinamide D (1), (E)-coscinamide D (2)—and four compounds isolated for the first time as natural products—lamellomorphamides A (3), B (4), C (5) and D (6). In addition, fifteen previously reported natural products were isolated, seven of which are seco analogs of hamacanthin alkaloids. The one sponge produces enantiomerically pure but opposite configurations of compounds that only differ in the number of bromines, suggesting enantio ergent biosynthesis. In addition, four compounds were isolated as partial racemates, suggesting these compounds are biosynthesized via two independent routes.
Publisher: Proceedings of the National Academy of Sciences
Date: 14-10-2019
Abstract: Agonists of the μ-opioid receptor (MOPr) are currently the gold standard for pain treatment. However, their therapeutic usage is greatly limited by side effects including respiratory depression, constipation, tolerance, and dependence. Functionally selective MOPr agonists that mediate their effects preferentially through G proteins rather than β-arrestin signaling are believed to produce fewer side effects. Here, we present the discovery of 3 unusual tetrapeptides with a unique stereochemical arrangement of hydrophobic amino acids from an Australian estuarine isolate of Penicillium species. Building on these natural templates we developed bilorphin, a potent and selective highly G protein-biased agonist of the MOPr. Further, through the addition of a simple sugar moiety, we generated bilactorphin that is an effective analgesic in vivo.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2022
DOI: 10.1038/S41429-021-00493-4
Abstract: Streptomyces sp. MST-91080 was isolated from a soil s le collected in Queensland, Australia. From this strain, yeppoonic acids A - D were purified and spectroscopically characterised. The yeppoonic acids are a family of diene enecarboxylic acids on a 1,2,4-trisubstituted benzene scaffold, structurally related to other Streptomyces secondary metabolites MF-EA-705α/β, NFAT-133 and the lorneic acids. Yeppoonic acids B and C show strong cytotoxicity against the NS-1 mouse myeloma cell line (IC
Publisher: Springer Science and Business Media LLC
Date: 17-06-2020
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.FITOTE.2017.10.014
Abstract: Macroalgae are a rich source of biologically active chemical ersity for pharmaceutical and agrichemical discovery. However, the ability to understand the complexities of their chemical ersity will dictate whether these natural products have a place in modern discovery paradigms. In this study, we examined the relationship between secondary metabolite production and biological activity for a cohort of 127 macroalgae s les collected from various locations across South Eastern Australia. Approximately 20% of the macroalgae s les showed high levels of chemical ersity and productivity, which also correlated strongly with bioactivity. These "talented" species represent sustainable sources of metabolites that may be readily harvested for large-scale production. At a taxonomic level, significant differences in metabolite production and ersity were observed between Chlorophyta, Rhodophyta and Phaeophyta. For each talented species, the cometabolite pattern was unique to that species, with closely related species within the same genus displaying very different profiles. Despite over 50years of investigation, we estimate that more than two-thirds of the chemical ersity of macroalgae remains unknown to science. By understanding the physicochemical properties and distribution patterns of metabolites, it is possible to make reasoned judgements about sustainable sourcing of macroalgae for biodiscovery.
Publisher: Elsevier BV
Date: 11-2013
Publisher: MDPI AG
Date: 16-06-2021
DOI: 10.3390/ANTIBIOTICS10060727
Abstract: Our recent focus on the “lost antibiotic” unguinol and related nidulin-family fungal natural products identified two semisynthetic derivatives, benzguinols A and B, with unexpected in vitro activity against Staphylococcus aureus isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen Staphylococcus pseudintermedius, with minimum inhibitory concentration (MIC) ranging 0.5–1 μg/mL. When combined with sub-inhibitory concentrations of colistin, the benzguinols demonstrated synergy against Gram-negative reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (MICs of 1–2 μg/mL in the presence of colistin), whereas the benzguinols alone had no activity. Administration of three intraperitoneal (IP) doses of 20 mg/kg benzguinol A or B to mice did not result in any obvious adverse clinical or pathological evidence of acute toxicity. Importantly, mice that received three 20 mg/kg IP doses of benzguinol A or B at 4 h intervals exhibited significantly reduced bacterial loads and longer survival times than vehicle-only treated mice in a bioluminescent S. aureus murine sepsis challenge model. We conclude that the benzguinols are potential candidates for further development for specific treatment of serious bacterial infections as both stand-alone antibiotics and in combination with existing antibiotic classes.
Publisher: Elsevier BV
Date: 12-2011
Publisher: Elsevier BV
Date: 09-2016
Publisher: Wiley
Date: 21-02-2008
Publisher: Springer Science and Business Media LLC
Date: 26-07-2022
DOI: 10.1038/S41429-022-00544-4
Abstract: Amycolatopsis sp. MST-135876 was isolated from soil collected from the riverbank of El Pont de Suert, Catalonia, Spain. Cultivation of MST-135876 on a range of media led to the discovery of a previously unreported dichlorinated cyclic hexapeptide, suertide A ( d -Ser, 5-Cl- d -Trp, 6-Cl- d -Trp, l -Ile, d -Val, d -Glu), featuring an unprecedented pair of adjacent 5/6-chlorotryptophan residues. Supplementing the growth medium with KBr resulted in production of the mono- and dibrominated analogues suertides B and C, respectively. Suertides A–C displayed selective activity against Bacillus subtilis (MIC 1.6 µg ml −1 ) and Staphylococcus aureus (MIC 3.1, 6.3, and 12.5 µg ml −1 , respectively), while suertides A and B showed appreciable activity against methicillin-resistant S. aureus (MIC 1.6 and 6.3 µg ml −1 , respectively).
Publisher: American Chemical Society (ACS)
Date: 10-09-2008
DOI: 10.1021/OL8016512
Abstract: Four new alkaloids have been isolated during chemical investigations into a southern Australian marine sponge, Stelletta sp. Detailed spectroscopic analysis, supported by chemical degradation and partial synthesis, permitted structure elucidation of bistellettazines A-C ( 1- 3), the first reported ex les of terpenyl-pyrrolizidine conjugates, and bistellettazole A ( 4), a unique cyclic terpenyl-imidazole conjugate. The alkaloids 1- 4 feature unprecedented carbon skeletons that are proposed to share a common convergent biosynthetic origin, arising via the biogenic equivalent of a Diels-Alder addition between two hypothetical polyenyl norsesquiterpene precursors.
Publisher: American Chemical Society (ACS)
Date: 08-11-2021
DOI: 10.1021/ACS.ORGLETT.1C03283
Abstract: Activation of a cryptic polyketide synthase gene cluster
Publisher: Elsevier BV
Date: 11-2005
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.BMCL.2009.01.064
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 ersity within the secretions of Australian cane toads is different to cane toads from overseas, being far more structurally erse than previously assumed. It is proposed that this variation is mediated by in situ bacterial biotransformation.
Publisher: Elsevier BV
Date: 10-2007
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.BMC.2013.04.061
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.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4OB00745J
Abstract: A rare class of oxanthromicin polyketides was isolated from a soil-derived Streptomyces sp. SAR-investigation showed that selected analogues can induce significant K-Ras plasma membrane mislocalisation and can synergise the K-Ras plasma membrane mislocalisation properties of staurosporine.
Publisher: Oxford University Press (OUP)
Date: 27-05-2023
Abstract: Building on a previously developed workflow for rapid and sensitive pathogen detection by qPCR, this work has established a s le treatment strategy that produces consistent quantification efficiencies (QEs) for C ylobacter jejuni against a complex and highly variable s le matrix from a suburban river. The in idual treatments most effective at minimizing the inhibitory effects of the s le matrix were pH buffering with HEPES (50 mM, pH 5.7) and addition of the surfactant Tween 20 (2% v/v). Unexpectedly, s le acidification (pH 4–5) resulting from the use of aged Tween 20 that had undergone partial hydrolysis, appeared to play a key role in enhancing QE. This effect could be replicated by direct pH adjustment with dilute hydrochloric acid and may be linked to the solubilization and removal of inhibitory particles at an acidic pH. While the effectiveness of each in idual treatment method varied, a combined treatment of either HEPES buffer + Tween 20, or direct pH adjustment + Tween 20, consistently produced QEs of 60%–70% and up to 100%, respectively, over a s ling period of one year. The consistency and scalability of this workflow make it a suitable alternative to culture-based ISO methods for detecting C ylobacter spp.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0OB01099E
Abstract: Stereo ergence in Nature encapsulates both enzymatic (biosynthetic) and non-enzymatic (chemical) ersification of natural product scaffolds arising from a single biosynthetic pathway.
Publisher: American Chemical Society (ACS)
Date: 19-03-2015
DOI: 10.1021/ACS.JNATPROD.5B00095
Abstract: Chemical analysis of an Australian marine-derived Streptomyces sp. (CMB-M0150) yielded two new anthracycline antibiotics, aranciamycins I (1) and J (2), as well as the previously reported aranciamycin A (3) and aranciamycin (4). The aranciamycins 1-4, identified by detailed spectroscopic analysis, were noncytotoxic when tested against selected Gram-negative bacteria and fungi (IC50 >30 μM) and exhibited moderate and selective cytotoxicity against Gram-positive bacteria (IC50 >1.1 μM) and a panel of human cancer cell lines (IC50 > 7.5 μM). Significantly, 1-4 were cytotoxic (IC50 0.7-1.7 μM) against the Mycobacterium tuberculosis surrogate M. bovis bacille Calmette-Guérin.
Publisher: PeerJ
Date: 29-11-2022
DOI: 10.7717/PEERJ.14414
Abstract: The leporid lagomorphs (rabbits and hares) are adapted to running and leaping (some more than others) and consequently have unique anatomical features that distinguish them from ochotonid lagomorphs (pikas) and from their rodent relatives. Two traits that have received some attention are fenestration of the lateral wall of the maxilla and facial tilting. These features are known to correlate with specialised locomotory form in that the faster running species will generally have fenestration that occupies the dorsal and the anteroventral surface of the maxillary corpus and a more acute facial tilt angle. Another feature is an intracranial joint that circumscribes the back of the skull, thought to facilitate skull mobility. This joint separates the anterior portion of the cranium (including the dentition, rostrum and orbit) from the posterior portion of the cranium (which encompasses the occipital and the auditory complex). Aside from the observation that the intracranial joint is absent in pikas (generalist locomotors) and appears more elaborate in genera with cursorial and saltatorial locomotory habits, the evolutionary history, biomechanical function and comparative anatomy of this feature in leporids lacks a comprehensive evaluation. The present work analysed the intracranial joint, facial tilting and lateral fenestration of the wall of the maxilla in the context of leporid evolutionary history using a Bayesian inference of phylogeny (18 genera, 23 species) and ancestral state reconstruction. These methods were used to gather information about the likelihood of the presence of these three traits in ancestral groups. Our phylogenetic analyses found it likely that the last common ancestor of living leporids had some facial tilting, but that the last common ancestor of all lagomorphs included in the dataset did not. We found that it was likely that the last common ancestor of living leporids had fenestration that occupies the dorsal, but not the anteroventral, surface of the maxillary corpus. We also found it likely that the last common ancestor of living leporids had an intracranial joint, but that the last common ancestor of all living lagomorphs did not. These findings provide a broader context to further studies of evolutionary history and will help inform the formulation and testing of functional hypotheses.
Publisher: American Chemical Society (ACS)
Date: 19-06-2018
DOI: 10.1021/ACS.JNATPROD.7B00816
Abstract: Chemical investigation of an Australian fungus, Aspergillus banksianus, led to the isolation of the major metabolite banksialactone A (1), eight new isochromanones, banksialactones B-I (2-9), two new isocoumarins, banksiamarins A and B (10 and 11), and the reported compounds, clearanol I (12), dothideomynone A (13), questin (14), and endocrocin (15). The structures of 1-11 were established by NMR spectroscopic data analysis, and the absolute configurations were determined from optical rotations and ECD spectra in conjunction with TD-DFT calculations. The secondary metabolite profile of A. banksianus is unusual, with the 11 most abundant metabolites belonging to a single isochromanone class. Conjugation of 1 with endocrocin, 5-methylorsellinic acid, 3,5-dimethylorsellinic acid, mercaptolactic acid, and an unknown methylthio source gave rise to five unprecedented biosynthetic hybrids, 5-9. The isolated compounds were tested for cytotoxicity, antibacterial, and antifungal activities, with hybrid metabolites 7-9 displaying weak cytotoxic and antibiotic activities.
Publisher: Public Library of Science (PLoS)
Date: 05-04-2017
Publisher: American Chemical Society (ACS)
Date: 09-10-2007
DOI: 10.1021/AC071518P
Abstract: The determination of free sulfhydryl groups is important in many aspects of biotechnology, such as measuring the coupling efficiency of thiol-reactive probes, assaying cysteine-containing haptens, and assaying reductase/thiol transferase activity, as well as in various aspects of the food industry. This is generally achieved colorimetrically using Ellman's reagent, although the assay is relatively insensitive and Ellman's reagent is unstable. In this paper, we describe a highly sensitive fluorometric assay for free sulfhydryl groups based on FRET, which we have used to develop a sensitive assay for glutathione reductase activity. The assay exploits the specific increase in fluorescence intensity that occurs at 520 nm when a probe containing two molecules of fluorescein linked via a disulfide group is cleaved by glutathione. The assay is 2 orders of magnitude more sensitive than the commonly used colorimetric glutathione reductase assay and has a greater dynamic range.
Publisher: Beilstein Institut
Date: 26-08-2019
DOI: 10.3762/BJOC.15.198
Abstract: Chemical investigation of the barley and wheat fungal pathogen Bipolaris sorokiniana BRIP10943 yielded four new sativene-type sesquiterpenoid natural products, bipolenins K–N ( 1 – 4 ), together with seven related known analogues ( 5 – 11 ), and a sesterterpenoid ( 12 ). Their structures were determined by detailed analysis of spectroscopic data, supported by TDDFT calculations and comparison with previously reported analogues. These compounds were evaluated for their phytotoxic activity against wheat seedlings and wheat seed germination. The putative biosynthetic relationships between the isolated sesquiterpenoids were also explored.
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/CH15488
Abstract: A soil survey conducted in southern Queensland, Australia, identified a novel isolate belonging to the genus Aspergillus subgenus Circumdati section Circumdati, Aspergillus kumbius FRR6049. Cultivation and fractionation of secondary metabolites from A. kumbius revealed a unique chemotype comprising three new bis-indolyl benzenoids, kumbicins A–C, and a new bis-indolyl benzoquinone, kumbicin D, along with the previously reported compounds asterriquinol D dimethyl ether, petromurins C and D, aspochracin, its N-demethyl analogue JBIR-15, and neohydroxyaspergillic acid. The structures of kumbicins A–D were assigned by detailed spectroscopic analysis. Kumbicin C was found to inhibit the growth of mouse myeloma cells (IC50 0.74 μg mL–1) and the Gram-positive bacterium Bacillus subtilis (MIC 1.6 μg mL–1).
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2CC01679F
Abstract: The discovery of a novel family of p -nitrobenzoylated piperazines from Aspergillus brevijanus revealed that the biosynthesis of p -nitrobenzoic acid in fungi is catalysed by a PABA synthase, an aminodeoxychorismate synthase and a cytochrome P450.
Publisher: American Chemical Society (ACS)
Date: 17-03-2020
DOI: 10.1021/JACS.0C01605
Publisher: MDPI AG
Date: 31-10-2005
DOI: 10.3390/10101292
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1OB00600B
Abstract: Biosynthetic mosaics and superclusters provide rare insights into the evolution of microbial chemical ersity.
Publisher: Royal Society of Chemistry
Date: 2016
Publisher: Wiley
Date: 06-12-2012
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8OB00545A
Abstract: Reinvestigating antibiotic scaffolds that were identified during the Golden Age of antibiotic discovery, but have long since been “forgotten”, has proven to be an effective strategy for delivering next-generation antibiotics capable of combatting multidrug-resistant superbugs.
Publisher: Elsevier BV
Date: 2013
Publisher: Royal Society of Chemistry
Date: 2016
Publisher: Elsevier BV
Date: 02-2012
Publisher: American Chemical Society (ACS)
Date: 02-09-2014
DOI: 10.1021/JO501501Z
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0OB02243H
Abstract: The hancockiamides are an unusual new family of N -cinnamoylated piperazines from the Australian soil fungus Aspergillus hancockii , originating from mixed nonribosomal peptide and phenylpropanoid pathways.
Publisher: Wiley
Date: 24-04-2012
Abstract: Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β) identified a Western Australian Didemnum species (CMB-02127) as a high-priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B-D as the major metabolites, together with six minor metabolites, the new ningalins E-G and the known hexacyclic pyrrole alkaloids lamellarins Z, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X-ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0SC01928C
Abstract: Reactivation of quiescent polyketide production in a domesticated lab strain.
Publisher: American Chemical Society (ACS)
Date: 10-09-2012
DOI: 10.1021/OL302051X
Abstract: An Aspergillus versicolor isolated from sediment collected from the Bohai Sea, China, yielded the new dimeric diketopiperazine brevianamide S (1), together with three new monomeric cometabolites, brevianamides T (2), U (3), and V (4). Structures were determined by detailed spectroscopic analysis. Brevianamide S exhibited selective antibacterial activity against Bacille Calmette-Guérin (BCG), suggestive of a new mechanism of action that could inform the development of next-generation antitubercular drugs.
Publisher: Wiley
Date: 05-12-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D2OB02332F
Abstract: The discovery of the resoruclins, new 3,5-dihydroxybenzoic acid containing macrolides for Steptomyces sp. MST-91080, and their putative biosynthetic pathway.
Publisher: American Chemical Society (ACS)
Date: 13-01-2017
DOI: 10.1021/ACS.JNATPROD.6B01038
Abstract: The isolation of bromotyrosine alkaloids, some of which are enantiomers of previously isolated compounds, has highlighted a possible enantio ergence in their biosynthesis. Two new (1, 2) and six known bromotyrosine alkaloids (4-9), and the enantiomer (10) of a known compound, have been isolated from a Western Australian marine sponge, Pseudoceratina cf. verrucosa. The compounds inhibited the growth of multidrug-resistant and methicillin-resistant Staphylococcus aureus with comparable activity to vancomycin. In addition, one possible artifact of extraction (3) containing an ethoxy group was isolated. From analysis of the known bromotyrosine alkaloids, a biogenesis is proposed that explains the formation of antipodal natural products within this family of sponges.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8SC02870B
Abstract: Formation of the three C–C bridges between the two naphthol monomers for elsinochrome ( 1 ) involves three distinct classes of oxidases.
Publisher: American Chemical Society (ACS)
Date: 16-12-2023
Publisher: American Chemical Society (ACS)
Date: 19-01-2023
Publisher: American Chemical Society (ACS)
Date: 22-09-2023
Publisher: American Chemical Society (ACS)
Date: 08-02-2019
DOI: 10.1021/ACS.ORGLETT.8B04042
Abstract: The burnettramic acids are a new class of antibiotics from an Australian fungus Aspergillus burnettii. The rare bola hiphilic scaffold consists of β-d-mannose linked to a pyrrolizidinedione unit via a 26-carbon chain. The most abundant metabolite displayed potent in vitro antifungal activity. Comparative genomics identified the hybrid PKS-NRPS bua gene cluster, which was verified by heterologous pathway reconstitution in Aspergillus nidulans.
Publisher: American Chemical Society (ACS)
Date: 05-08-2009
DOI: 10.1021/OL901466R
Abstract: Chemical analysis of a Streptomyces sp. (CMB-MQ030) isolated from a Fijian marine sediment yielded two new diketopiperazines, naseseazines A and B (1, 2), featuring a new dimeric framework. Structures were determined by detailed spectroscopic analysis and C(3) Marfey's analysis.
Publisher: Elsevier BV
Date: 04-2012
Publisher: American Chemical Society (ACS)
Date: 07-12-2020
Publisher: American Chemical Society (ACS)
Date: 02-03-2020
Publisher: MDPI AG
Date: 29-01-2019
DOI: 10.3390/MD17020081
Abstract: The recent success of small-molecule kinase inhibitors as anticancer drugs has generated significant interest in their application to other clinical areas, such as disorders of the central nervous system (CNS). However, most kinase inhibitor drug candidates investigated to date have been ineffective at treating CNS disorders, mainly due to poor blood–brain barrier (BBB) permeability. It is, therefore, imperative to evaluate new chemical entities for both kinase inhibition and BBB permeability. Over the last 35 years, marine biodiscovery has yielded 471 natural products reported as kinase inhibitors, yet very few have been evaluated for BBB permeability. In this study, we revisited these marine natural products and predicted their ability to cross the BBB by applying freely available open-source chemoinformatics and machine learning algorithms to a training set of 332 previously reported CNS-penetrant small molecules. We evaluated several regression and classification models, and found that our optimised classifiers (random forest, gradient boosting, and logistic regression) outperformed other models, with overall cross-validated model accuracies of 80%–82% and 78%–80% on external testing. All 3 binary classifiers predicted 13 marine-derived kinase inhibitors with appropriate physicochemical characteristics for BBB permeability.
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0OB00654H
Abstract: Chemical analysis of fermentation products from two Australian Streptomyces isolates yielded all four known and twelve new ex les of the rare reveromycin class of polyketide spiroketals, including hemi-succinates, hemi-fumarates and hemi-furanoates. Reveromycins were identified with the aid of HPLC-DAD-MS and HPLC-DAD-SPE-NMR methodology, and structures were assigned by detailed spectroscopic analysis. The structural and mechanistic requirements for an unprecedented hemi-succinate : ketal-succinyl equilibrium were defined and provided a basis for proposing that reveromycin 4'-methyl esters and 5,6-spiroketals were artifacts. A plausible reveromycin polyketide biosynthesis is proposed, requiring a 2-methylsuccinyl-CoA starter unit, with flexible incorporation of a C(6-8) polyketide chain extension and diacid esterification units. Structure activity relationship investigations by co-metabolites were used to assess the anticancer, antibacterial and antifungal properties of reveromycins.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2014
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1OB01766G
Abstract: Burnettiene A is a novel cytotoxic tridecaketide decalin polyketide from Aspergillus burnettii . Its biosynthesis was elucidated by heterologous expression in fungi.
Publisher: MDPI AG
Date: 15-06-2017
DOI: 10.3390/MD15060177
Abstract: Two new steroids, crellasterones A (1) and B (2), together with the previously reported compound chalinasterol (3) and several nucleosides (4–7), were isolated from the sponge Crella incrustans, collected in New Caledonia. The structures of the new compounds were established by extensive NMR and mass spectroscopic analysis and revealed unprecedented marine natural products with a ring-contracted A-norsterone nucleus and 2-hydroxycyclopentenone chromophore. The absolute configurations were derived from electronic circular dichroism (ECD) measurements in conjunction with high-level density functional theory (DFT) calculations.
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C0OB00267D
Abstract: A Streptomyces sp. isolated from a shallow water sediment s le collected off Heron Island, Australia, afforded three new polyketide macrolactams, heronamides A-C (1-3). Structures were assigned to the heronamides on the basis of detailed spectroscopic analysis, chemical derivatization and biosynthetic considerations. A plausible biosynthetic pathway is proposed in which key carbocyclic ring transformations proceed via an unprecedented synchronized tandem electrocyclization. This biosynthesis provides a framework for the assignment of complete relative configurations across all heronamides, and inspires an attractive biomimetic strategy for future total syntheses. Heronamide C elicits a dramatic and reversible non-cytotoxic effect on mammalian cell morphology.
Publisher: American Chemical Society (ACS)
Date: 11-03-2014
DOI: 10.1021/OL5003913
Abstract: A marine-derived Streptomyces sp. (CMB-M0244) isolated from a sediment collected off South Molle Island, Queensland, produced mollemycin A (1) as a new first in class glyco-hexadepsipeptide-polyketide. The structure of 1 was assigned by detailed spectroscopic analysis, supported by chemical derivatization and degradation, and C3 Marfey's analysis. Mollemycin A (1) exhibits exceptionally potent and selective growth inhibitory activity against Gram-positive and Gram-negative bacteria (IC50 10-50 nM) and drug-sensitive (3D7 IC50 7 nM) and multidrug-resistant (Dd2 IC50 9 nM) clones of the malaria parasite Plasmodium falciparum.
Publisher: CSIRO Publishing
Date: 2010
DOI: 10.1071/CH09645
Abstract: Chemical fractionation of a southern Australian marine sponge, Trachycladus laevispirulifer, yielded 9-(5′-deoxy-5′-thio-β-d-xylofuranosyl)adenine disulfide as the first recorded natural occurrence of a nucleoside disulfide, and only the second of a xylo-nucleoside. Structure elucidation of the disulfide was achieved by detailed spectroscopic analysis and comparison to synthetic model compounds. The antibacterial, antifungal, and anticancer properties of the disulfide are documented and the literature surrounding natural and synthetic thionucleosides is reviewed.
Publisher: American Chemical Society (ACS)
Date: 18-09-2018
DOI: 10.1021/ACS.ORGLETT.8B02617
Abstract: A biosynthetic gene cluster that is significantly upregulated in the fungal wheat pathogen Parastagonospora nodorum during plant infection was reconstructed heterologously in Aspergillus nidulans. This led to the discovery of five new α-pyrone polyketides, alternapyrones B-F (2-6). Compounds 5 and 6, which contain a highly substituted dihydrofuran, exhibited phytotoxicity on wheat seed germination. It is demonstrated that only three enzymes, one highly reducing polyketide synthase and two multifunctional P450 oxygenases, are needed to synthesize the structurally complex products.
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BMC.2009.08.039
Abstract: Reverse chemical proteomics using T7 phage display is a powerful technique for identifying cellular receptors of biologically active small molecules. However, to date this method has generally been limited to cDNA libraries constructed from mRNA isolated from eukaryotes. In this paper, we describe the construction of the first prokaryotic T7 phage display libraries from randomly digested Pseudomonas stutzeri and Vibrio fischeri gDNA, as well as a plant cDNA library from Arabidopsis thaliana. We also describe the use of T7 phage display to identify novel proteins from environmental DNA s les using biotinylated FK506 as a model affinity probe.
Publisher: American Chemical Society (ACS)
Date: 22-04-2011
DOI: 10.1021/OL200904V
Abstract: An Australian marine sediment-derived isolate, Nocardiopsis sp. (CMB-M0232), yielded a new class of prenylated diketopiperazine, indicative of the action of a uniquely regioselective diketopiperazine indole prenyltransferase. The bridged scaffold of nocardioazine A proved to be a noncytotoxic inhibitor of the membrane protein efflux pump P-glycoprotein, reversing doxorubicin resistance in a multidrug resistant colon cancer cell.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5NP00128E
Abstract: A description of the T7 phage biopanning procedure is provided with tips and advice suitable for setup in a chemistry laboratory.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.CHEMBIOL.2012.05.019
Abstract: Protein prenylation is required for membrane anchorage of small GTPases. Correct membrane targeting is essential for their biological activity. Signal output of the prenylated proto-oncogene Ras in addition critically depends on its organization into nanoscale proteolipid assemblies of the plasma membrane, so called nanoclusters. While protein prenylation is an established drug target, only a handful of nanoclustering inhibitors are known, partially due to the lack of appropriate assays to screen for such compounds. Here, we describe three cell-based high-throughput screening amenable Förster resonance energy transfer NANOclustering and Prenylation Sensors (NANOPS) that are specific for Ras, Rho, and Rab proteins. Rab-NANOPS provides the first evidence for nanoclustering of Rab proteins. Using NANOPS in a cell-based chemical screen, we now identify macrotetrolides, known ionophoric antibiotics, as submicromolar disruptors of Ras nanoclustering and MAPK signaling.
Publisher: Beilstein Institut
Date: 05-11-2019
DOI: 10.3762/BJOC.15.256
Abstract: Chemical investigation of an undescribed Australian fungus, Aspergillus nanangensis , led to the identification of the nanangenines – a family of seven new and three previously reported drimane sesquiterpenoids. The structures of the nanangenines were elucidated by detailed spectroscopic analysis supported by single crystal X-ray diffraction studies. The compounds were assayed for in vitro activity against bacteria, fungi, mammalian cells and plants. Bioinformatics analysis, including comparative analysis with other acyl drimenol-producing Aspergilli, led to the identification of a putative nanangenine biosynthetic gene cluster that corresponds to the proposed biosynthetic pathway for nanangenines.
Publisher: American Chemical Society (ACS)
Date: 26-02-2009
DOI: 10.1021/NP800777F
Abstract: An Australian marine-derived isolate of Aspergillus versicolor (MST-MF495) yielded the known fungal metabolites sterigmatocystin, violaceol I, violaceol II, diorcinol, (-)-cyclopenol, and viridicatol, along with a new alkaloid, cottoquinazoline A (1), and two new cyclopentapeptides, cotteslosins A (2) and B (3). Structures for 1-3 and the known compounds were determined by spectroscopic analysis. The absolute configurations of 1-3 were addressed by chemical degradation and application of the C(3) Marfey's method. The use of "cellophane raft" high-nutrient media as a device for up-regulating secondary metabolite ersity in marine-derived fungi is discussed. The antibacterial properties displayed by A. versicolor (MST-MF495) were attributed to the phenols violaceol I, violaceol II, and diorcinol, while cotteslosins 2 and 3 were identified as weak cytotoxic agents.
Publisher: American Chemical Society (ACS)
Date: 08-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0OB02460K
Abstract: Semisynthetic unguinol derivatives showed potent activity against a panel of methicillin-resistant Staphylococcus aureus strains and are promising candidates for further development.
Start Date: 2022
End Date: 2025
Funder: Australian Research Council
View Funded ActivityStart Date: 2013
End Date: 2017
Funder: Australian Research Council
View Funded ActivityStart Date: 2021
End Date: 2024
Funder: Australian Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: Australian Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: Australian Research Council
View Funded ActivityStart Date: 04-2014
End Date: 06-2019
Amount: $752,788.00
Funder: Australian Research Council
View Funded ActivityStart Date: 01-2021
End Date: 03-2024
Amount: $543,738.00
Funder: Australian Research Council
View Funded ActivityStart Date: 05-2022
End Date: 05-2025
Amount: $790,268.00
Funder: Australian Research Council
View Funded ActivityStart Date: 01-2013
End Date: 03-2017
Amount: $285,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 06-2018
End Date: 06-2024
Amount: $423,252.00
Funder: Australian Research Council
View Funded Activity