Publications by authors named "Andrew M Piggott"

55 Publications

Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections.

Antibiotics (Basel) 2021 Jun 16;10(6). Epub 2021 Jun 16.

Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, Australia.

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 isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen , 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 , , and (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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antibiotics10060727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233939PMC
June 2021

Chlorinated metabolites from Streptomyces sp. highlight the role of biosynthetic mosaics and superclusters in the evolution of chemical diversity.

Org Biomol Chem 2021 Jul 28;19(27):6147-6159. Epub 2021 Jun 28.

Department of Molecular Sciences, Macquarie University, NSW 2109, Australia.

LCMS-guided screening of a library of biosynthetically talented bacteria and fungi identified Streptomyces sp. MST- as a prolific producer of chlorinated metabolites. We isolated and characterised six new and nine reported compounds from MST-, belonging to three discrete classes - the depsipeptide svetamycins, the indolocarbazole borregomycins and the aromatic polyketide anthrabenzoxocinones. Following genome sequencing of MST-, we describe, for the first time, the svetamycin biosynthetic gene cluster (sve), its mosaic structure and its relationship to several distantly related gene clusters. Our analysis of the sve cluster suggested that the reported stereostructures of the svetamycins may be incorrect. This was confirmed by single-crystal X-ray diffraction analysis, allowing us to formally revise the absolute configurations of svetamycins A-G. We also show that the borregomycins and anthrabenzoxocinones are encoded by a single supercluster (bab) implicating superclusters as potential nucleation points for the evolution of biosynthetic gene clusters. These clusters highlight how individual enzymes and functional subclusters can be co-opted during the formation of biosynthetic gene clusters, providing a rare insight into the poorly understood mechanisms underpinning the evolution of chemical diversity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1ob00600bDOI Listing
July 2021

Production of novel pladienolide analogues through native expression of a pathway-specific activator.

Chem Sci 2020 Jul 17;11(31):8249-8255. Epub 2020 Jul 17.

Department of Molecular Microbiology, John Innes Centre Norwich Research Park Norwich NR4 7UH UK

Aberrant splicing of pre-mRNA is implicated in many human genetic disorders. Small molecules that target the spliceosome are important leads as therapeutics and research tools, and one compound of significant interest is the polyketide natural product pladienolide B. Here, we describe the reactivation of quiescent pladienolide B production in the domesticated lab strain AS6200 by overexpression of the pathway-specific activator PldR. The resulting dysregulation of the biosynthetic genes led to the accumulation and isolation of five additional intermediate or shunt metabolites of pladienolide B biosynthesis, including three previously unreported congeners. These compounds likely comprise the entire pladienolide biosynthetic pathway and demonstrate the link between polyketide tailoring reactions and bioactivity, particularly the importance of the 18,19-epoxide. Each congener demonstrated specific inhibitory activity against mammalian cell lines, with successive modifications leading to increased activity (IC: 8 mM to 5 μM).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0sc01928cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163091PMC
July 2020

TriTOX: A novel Trichomonas vaginalis assay platform for high-throughput screening of compound libraries.

Int J Parasitol Drugs Drug Resist 2021 Apr 10;15:68-80. Epub 2021 Feb 10.

Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. Electronic address:

Trichomonas vaginalis is a neglected urogenital parasitic protist that causes 170 million cases of trichomoniasis annually, making it the most prevalent non-viral, sexually transmitted disease. Trichomoniasis treatment relies on nitroheterocyclics, such as metronidazole. However, with increasing drug-resistance, there is an urgent need for novel anti-trichomonals. Little progress has been made to translate anti-trichomonal research into commercialised therapeutics, and the absence of a standardised compound-screening platform is the immediate stumbling block for drug-discovery. Herein, we describe a simple, cost-effective growth assay for T. vaginalis and the related Tritrichomonas foetus. Tracking changes in pH were a valid indicator of trichomonad growth (T. vaginalis and T. foetus), allowing development of a miniaturised, chromogenic growth assay based on the phenol red indicator in 96- and 384-well microtiter plate formats. The outputs of this assay can be quantitatively and qualitatively assessed, with consistent dynamic ranges based on Z' values of 0.741 and 0.870 across medium- and high-throughput formats, respectively. We applied this high-throughput format within the largest pure-compound microbial metabolite screen (812 compounds) for T. vaginalis and identified 43 hit compounds. We compared these identified compounds to mammalian cell lines, and highlighted extensive overlaps between anti-trichomonal and anti-tumour activity. Lastly, observing nanomolar inhibition of T. vaginalis by fumagillin, and noting this compound has reported activity in other protists, we performed in silico analyses of the interaction of fumagillin with its molecular target methionine aminopeptidase 2 for T. vaginalis, Giardia lamblia and Entamoeba histolytica, highlighting potential for fumagillin as a broad-spectrum anti-protistal against microaerophilic protists. Together, this new platform will accelerate drug-discovery efforts, underpin drug-resistance screening in trichomonads, and contributing to a growing body of evidence highlighting the potential of microbial natural products as novel anti-protistals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpddr.2021.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897990PMC
April 2021

Semisynthesis and biological evaluation of a focused library of unguinol derivatives as next-generation antibiotics.

Org Biomol Chem 2021 02 14;19(5):1022-1036. Epub 2021 Jan 14.

Department of Molecular Sciences, Macquarie University, NSW 2109, Australia.

In this study, we report the semisynthesis and in vitro biological evaluation of thirty-four derivatives of the fungal depsidone antibiotic, unguinol. Initially, the semisynthetic modifications were focused on the two free hydroxy groups (3-OH and 8-OH), the three free aromatic positions (C-2, C-4 and C-7), the butenyl side chain and the depsidone ester linkage. Fifteen first-generation unguinol analogues were synthesised and screened against a panel of bacteria, fungi and mammalian cells to formulate a basic structure activity relationship (SAR) for the unguinol pharmacophore. Based on the SAR studies, we synthesised a further nineteen second-generation analogues, specifically aimed at improving the antibacterial potency of the pharmacophore. In vitro antibacterial activity testing of these compounds revealed that 3-O-(2-fluorobenzyl)unguinol and 3-O-(2,4-difluorobenzyl)unguinol showed potent activity against both methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MIC 0.25-1 μg mL) and are promising candidates for further development in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0ob02460kDOI Listing
February 2021

Rechoreographing Enterocin's Ballet of Isomers: Structure Revision of Enterocins C, D, and F.

Org Lett 2020 12 7;22(24):9688-9692. Epub 2020 Dec 7.

Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia.

The tricyclic scaffold of the bacterial polyketide enterocin was recently shown to undergo stereodiversification through a series of abiotic isomerizations, described metaphorically as a "ballet of isomers". However, some confusion remains regarding the exact nature of these interconversions, with two independent reports proposing different reaction mechanisms and intermediates. Herein, we have rechoreographed enterocin's ballet of isomers to provide a unified mechanism and revised the structures reported for enterocins C, D, and F.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.0c03745DOI Listing
December 2020

Hancockiamides: phenylpropanoid piperazines from are biosynthesised by a versatile dual single-module NRPS pathway.

Org Biomol Chem 2021 01;19(3):587-595

School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia.

The hancockiamides are an unusual new family of N-cinnamoylated piperazines from the Australian soil fungus Aspergillus hancockii. Genomic analyses of A. hancockii identified a biosynthetic gene cluster (hkm) of 12 genes, including two single-module nonribosomal peptide synthetase (NRPS) genes. Heterologous expression of the hkm cluster in A. nidulans confirmed its role in the biosynthesis of the hancockiamides. We further demonstrated that a novel cytochrome P450, Hkm5, catalyses the methylenedioxy bridge formation, and that the PAL gene hkm12 is dispensable, but contributes to increased production of the cinnamoylated hancockiamides. In vitro enzymatic assays and substrate feeding studies demonstrated that NRPS Hkm11 activates and transfers trans-cinnamate to the piperazine scaffold and has flexibility to accept bioisosteric thienyl and furyl analogues. This is the first reported cinnamate-activating fungal NRPS. Expression of a truncated cluster lacking the acetyltransferase gene led to seven additional congeners, including an unexpected family of 2,5-dibenzylpiperazines. These pleiotropic effects highlight the plasticity of the pathway and the power of this approach for accessing novel natural product scaffolds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0ob02243hDOI Listing
January 2021

Comprehensive chemotaxonomic and genomic profiling of a biosynthetically talented Australian fungus, Aspergillus burnettii sp. nov.

Fungal Genet Biol 2020 10 20;143:103435. Epub 2020 Jul 20.

Department of Molecular Sciences, Macquarie University, NSW 2109, Australia. Electronic address:

Aspergillus burnettii is a new species belonging to the A. alliaceus clade in Aspergillus subgenus Circumdati section Flavi isolated from peanut-growing properties in southern Queensland, Australia. A. burnettii is a fast-growing, floccose fungus with distinctive brown conidia and is a talented producer of biomass-degrading enzymes and secondary metabolites. Chemical profiling of A. burnettii revealed the metabolites ochratoxin A, kotanins, isokotanins, asperlicin E, anominine and paspalinine, which are common to subgenus Circumdati, together with burnettiene A, burnettramic acids, burnettides, and high levels of 14α-hydroxypaspalinine and hirsutide. The genome of A. burnettii was sequenced and an annotated draft genome is presented. A. burnettii is rich in secondary metabolite biosynthetic gene clusters, containing 51 polyketide synthases, 28 non-ribosomal peptide synthetases and 19 genes related to terpene biosynthesis. Functional annotation of digestive enzymes of A. burnettii and A. alliaceus revealed overlapping carbon utilisation profiles, consistent with a close phylogenetic relationship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fgb.2020.103435DOI Listing
October 2020

The chemical gymnastics of enterocin: evidence for stereodivergence in Nature.

Org Biomol Chem 2020 Aug;18(30):5879-5890

Department of Molecular Sciences, Macquarie University, NSW 2109, Australia.

Stereodivergence in Nature encapsulates both enzymatic (biosynthetic) and non-enzymatic (chemical) diversification of natural product scaffolds arising from a single biosynthetic pathway. Herein, we report a fascinating example of stereodivergence for the bacterial polyketide enterocin, which we observed to undergo a series of facile skeletal rearrangements in solution, leading to four distinct isomeric structures. The final distribution of the four isomers was found to be highly sensitive to the conditions used, including solvent, temperature and pH. In this study, we have investigated the kinetics of these isomeric conversions, and using a combination of DFT and thermochemical calculations, were able to establish a mechanism detailing a concerted rearrangement and an unusual "gymnastic" sequence of pseudo-chair-boat conformational interconversions. In addition to these kinetic and mechanistic studies, we also performed a semisynthetic study aimed at stabilising the enterocin scaffold. In total, seven analogues of enterocin were synthesised and investigated for their stability and in vitro activity against a panel of bacteria, fungi, plants and mammalian cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0ob01099eDOI Listing
August 2020

Conglobatins B-E: cytotoxic analogues of the C-symmetric macrodiolide conglobatin.

J Antibiot (Tokyo) 2020 11 17;73(11):756-765. Epub 2020 Jun 17.

Department of Molecular Sciences, Macquarie University, North Ryde, Sydney, NSW, 2109, Australia.

Chemical investigation of a previously unreported indigenous Australian Streptomyces strain MST-91080 has identified six novel analogues related to the oxazole-pendanted macrodiolide, conglobatin. Phylogenetic analysis of the 16S rRNA gene sequence identified MST-91080 as a species of Streptomyces, distinct from reported conglobatin producer, Streptomyces conglobatus ATCC 31005. Conglobatins B-E diverge from conglobatin through differing patterns of methylation on the macrodiolide skeleton. The altered methyl positions suggest a deviation from the published biosynthetic pathway, which proposed three successive methylmalonyl-CoA extender unit additions to the conglobatin monomer. Conglobatins B1, C1 and C2 exhibited more potent cytotoxic activity selectively against the NS-1 myeloma cell line (IC 0.084, 1.05 and 0.45 µg ml, respectively) compared with conglobatin (IC 1.39 µg ml).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41429-020-0332-3DOI Listing
November 2020

Biosynthesis of a New Benzazepine Alkaloid Nanangelenin A from Involves an Unusual l-Kynurenine-Incorporating NRPS Catalyzing Regioselective Lactamization.

J Am Chem Soc 2020 04 31;142(15):7145-7152. Epub 2020 Mar 31.

Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia.

1-Benzazepine is a pharmaceutically important scaffold but is rare among natural products. Nanangelenin A (), containing an unprecedented 3,4-dihydro-1-benzazepine-2,5-dione--prenyl--acetoxy-anthranilamide scaffold, was isolated from a novel species of Australian fungus, . Genomic and retrobiosynthetic analyses identified a putative nonribosomal peptide synthetase (NRPS) gene cluster (). The detailed biosynthetic pathway to was established by heterologous pathway reconstitution in , which led to biosynthesis of intermediates nanagelenin B-F (- and ). We demonstrated that the NRPS NanA incorporates anthranilic acid (Ant) and l-kynurenine (l-Kyn), which is supplied by a dedicated indoleamine-2,3-dioxygenase NanC encoded in the gene cluster. Using heterologous assays and mutagenesis, we demonstrated that the C-terminal condensation (C) and thiolation (T) domains of NanA are responsible for the regioselective cyclization of the tethered Ant-l-Kyn dipeptide to form the unusual benzazepine scaffold in . We also showed that NanA-C catalyzes the regioselective cyclization of a surrogate synthetic substrate, Ant-l-Kyn--acetylcysteamine, to give the benzazepine scaffold, while spontaneous cyclization of the dipeptide yielded the alternative kinetically favored benzodiazepine scaffold. The discovery of and the characterization of NanA have expanded the chemical and functional diversities of fungal NRPSs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.0c01605DOI Listing
April 2020

Talauxins: Hybrid Phenalenone Dimers from .

J Nat Prod 2020 04 2;83(4):1051-1060. Epub 2020 Mar 2.

Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia.

Cultivation and extraction of the fungus led to the isolation of five new oxyphenalenone-amino acid hybrids, which were named talauxins E, Q, V, L, and I based on the corresponding one-letter amino acid codes, along with their putative biosynthetic precursor, duclauxin. The rapid reaction of duclauxin with amino acids to produce talauxins was demonstrated in vitro and exploited to generate a small library of natural and unnatural talauxins. Talauxin V was shown to undergo spontaneous elimination of methyl acetate to yield the corresponding neoclauxin scaffold. This process was modeled using density functional theory calculations, revealing a dramatic change in conformation resulting from the elimination of methyl acetate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.9b01066DOI Listing
April 2020

Bisindole Alkaloids from a New Zealand Deep-Sea Marine Sponge .

Mar Drugs 2019 Dec 4;17(12). Epub 2019 Dec 4.

Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia.

Chemical investigation of the secondary metabolites of a rare New Zealand deep-sea sponge, , resulted in the isolation of twenty-one indole alkaloids, including two new bisindoles-()-coscinamide D (), ()-coscinamide D ()-and four compounds isolated for the first time as natural products-lamellomorphamides A (), B (), C () and D (). 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 enantiodivergent biosynthesis. In addition, four compounds were isolated as partial racemates, suggesting these compounds are biosynthesized via two independent routes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md17120683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950519PMC
December 2019

Nanangenines: drimane sesquiterpenoids as the dominant metabolite cohort of a novel Australian fungus, .

Beilstein J Org Chem 2019 5;15:2631-2643. Epub 2019 Nov 5.

Department of Molecular Sciences, Macquarie University, NSW 2109, Australia.

Chemical investigation of an undescribed Australian fungus, , 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3762/bjoc.15.256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880815PMC
November 2019

A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor.

Proc Natl Acad Sci U S A 2019 10 14;116(44):22353-22358. Epub 2019 Oct 14.

Discipline of Pharmacology, School of Medical Sciences, University of Sydney, NSW 2006, Australia;

An Australian estuarine isolate of sp. MST-MF667 yielded 3 tetrapeptides named the bilaids with an unusual alternating LDLD chirality. Given their resemblance to known short peptide opioid agonists, we elucidated that they were weak ( low micromolar) μ-opioid agonists, which led to the design of bilorphin, a potent and selective μ-opioid receptor (MOPr) agonist ( 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit β-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting β-arrestin, with no receptor internalization. Importantly, bilorphin exhibits a similar G protein bias to oliceridine, a small nonpeptide with improved overdose safety. Molecular dynamics simulations of bilorphin and the strongly arrestin-biased endomorphin-2 with the MOPr indicate distinct receptor interactions and receptor conformations that could underlie their large differences in bias. Whereas bilorphin is systemically inactive, a glycosylated analog, bilactorphin, is orally active with similar in vivo potency to morphine. Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1908662116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825270PMC
October 2019

Bipolenins K-N: New sesquiterpenoids from the fungal plant pathogen .

Beilstein J Org Chem 2019 26;15:2020-2028. Epub 2019 Aug 26.

School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia.

Chemical investigation of the barley and wheat fungal pathogen BRIP10943 yielded four new sativene-type sesquiterpenoid natural products, bipolenins K-N (-), together with seven related known analogues (-), and a sesterterpenoid (). 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3762/bjoc.15.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720731PMC
August 2019

Heterologous biosynthesis of elsinochrome A sheds light on the formation of the photosensitive perylenequinone system.

Chem Sci 2019 Feb 22;10(5):1457-1465. Epub 2018 Nov 22.

School of Molecular Sciences , University of Western Australia , Perth , WA 6009 , Australia . Email:

Perylenequinones are a class of aromatic polyketides characterised by a highly conjugated pentacyclic core, which confers them with potent light-induced bioactivities and unique photophysical properties. Despite the biosynthetic gene clusters for the perylenequinones elsinochrome A (), cercosporin () and hypocrellin A () being recently identified, key biosynthetic aspects remain elusive. Here, we first expressed the intact gene cluster encoding from the wheat pathogen heterologously in on a yeast-fungal artificial chromosome (YFAC). This led to the identification of a novel flavin-dependent monooxygenase, ElcH, responsible for oxidative enolate coupling of a perylenequinone intermediate to the hexacyclic dihydrobenzo()perylenequinone in . In the absence of ElcH, the perylenequione intermediate formed a hexacyclic cyclohepta()perylenequinone system an intramolecular aldol reaction resulting in and a novel hypocrellin with opposite helicity to . Theoretical calculations supported that and resulted from atropisomerisation upon formation of the 7-membered ring. Using a bottom-up pathway reconstruction approach on a tripartite YFAC system developed in this study, we uncovered that both a berberine bridge enzyme-like oxidase ElcE and a laccase-like multicopper oxidase ElcG are involved in the double coupling of two naphthol intermediates to form the perylenequinone core. Gene swapping with the homologs from the biosynthetic pathway of showed that cognate pairing of the two classes of oxidases is required for the formation of the perylenequinone core, suggesting the involvement of protein-protein interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8sc02870bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354827PMC
February 2019

Discovery and Heterologous Biosynthesis of the Burnettramic Acids: Rare PKS-NRPS-Derived Bolaamphiphilic Pyrrolizidinediones from an Australian Fungus, Aspergillus burnettii.

Org Lett 2019 03 8;21(5):1287-1291. Epub 2019 Feb 8.

Department of Molecular Sciences , Macquarie University , Sydney , New South Wales 2109 , Australia.

The burnettramic acids are a new class of antibiotics from an Australian fungus Aspergillus burnettii. The rare bolaamphiphilic 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.8b04042DOI Listing
March 2019

Predicting Blood⁻Brain Barrier Permeability of Marine-Derived Kinase Inhibitors Using Ensemble Classifiers Reveals Potential Hits for Neurodegenerative Disorders.

Mar Drugs 2019 Jan 29;17(2). Epub 2019 Jan 29.

Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md17020081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410078PMC
January 2019

Chemical Ecogenomics-Guided Discovery of Phytotoxic α-Pyrones from the Fungal Wheat Pathogen Parastagonospora nodorum.

Org Lett 2018 10 18;20(19):6148-6152. Epub 2018 Sep 18.

School of Molecular Sciences , The University of Western Australia , Perth , WA 6009 , Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.8b02617DOI Listing
October 2018

Banksialactones and Banksiamarins: Isochromanones and Isocoumarins from an Australian Fungus, Aspergillus banksianus.

J Nat Prod 2018 07 19;81(7):1517-1526. Epub 2018 Jun 19.

Department of Molecular Sciences , Macquarie University , Sydney , NSW 2109 , Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.7b00816DOI Listing
July 2018

Expanding antibiotic chemical space around the nidulin pharmacophore.

Org Biomol Chem 2018 04;16(16):3038-3051

Department of Molecular Sciences, Macquarie University, NSW 2109, Australia.

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. In this study, we have revisited the trichloro-substituted depsidone, nidulin, as a selective and unexploited antibiotic lead produced by the fungus Aspergillus unguis. Manipulation of halide ion concentration proved to be a powerful tool for modulating secondary metabolite production and triggering quiescent pathways in A. unguis. Supplementation of the culture media with chloride resulted in a shift in co-metabolite profile to dichlorounguinols and nornidulin at the expense of the non-chlorinated parent, unguinol. Surprisingly, only marginal enhancement of nidulin was observed, suggesting O-methylation may be rate-limiting. Similarly, supplementation of the media with bromide led to the production of the corresponding bromo-analogues, but also resulted in a novel family of depsides, the unguidepsides. Unexpectedly, depletion of chloride from the media halted the biosynthesis of the non-chlorinated parent compound, unguinol, and redirected biosynthesis to a novel family of ring-opened analogues, the unguinolic acids. Supplementation of the media with a range of unnatural salicylic acids failed to yield the corresponding nidulin analogues, suggesting the compounds may be biosynthesised by a single polyketide synthase. In total, 12 new and 11 previously reported nidulin analogues were isolated, characterised and assayed for in vitro activity against a panel of bacteria, fungi and mammalian cells, providing a comprehensive structure-activity profile for the nidulin scaffold.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8ob00545aDOI Listing
April 2018

A study of the chemical diversity of macroalgae from South Eastern Australia.

Fitoterapia 2018 Apr 25;126:53-64. Epub 2017 Oct 25.

Department of Chemistry and Biomolecular Sciences, Macquarie University, NSW 2109, Australia. Electronic address:

Macroalgae are a rich source of biologically active chemical diversity for pharmaceutical and agrichemical discovery. However, the ability to understand the complexities of their chemical diversity 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 samples collected from various locations across South Eastern Australia. Approximately 20% of the macroalgae samples showed high levels of chemical diversity 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 diversity 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 diversity 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fitote.2017.10.014DOI Listing
April 2018

Crellasterones A and B: A-Norsterol Derivatives from the New Caledonian Sponge Crella incrustans.

Mar Drugs 2017 Jun 15;15(6). Epub 2017 Jun 15.

Department of Chemistry & Biomolecular Sciences, Macquarie University, Sydney NSW 2109, Australia.

Two new steroids, crellasterones A () and B (), together with the previously reported compound chalinasterol () and several nucleosides (-), were isolated from the sponge , 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md15060177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484127PMC
June 2017

Aspergillus hancockii sp. nov., a biosynthetically talented fungus endemic to southeastern Australian soils.

PLoS One 2017 5;12(4):e0170254. Epub 2017 Apr 5.

Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney NSW, Australia.

Aspergillus hancockii sp. nov., classified in Aspergillus subgenus Circumdati section Flavi, was originally isolated from soil in peanut fields near Kumbia, in the South Burnett region of southeast Queensland, Australia, and has since been found occasionally from other substrates and locations in southeast Australia. It is phylogenetically and phenotypically related most closely to A. leporis States and M. Chr., but differs in conidial colour, other minor features and particularly in metabolite profile. When cultivated on rice as an optimal substrate, A. hancockii produced an extensive array of 69 secondary metabolites. Eleven of the 15 most abundant secondary metabolites, constituting 90% of the total area under the curve of the HPLC trace of the crude extract, were novel. The genome of A. hancockii, approximately 40 Mbp, was sequenced and mined for genes encoding carbohydrate degrading enzymes identified the presence of more than 370 genes in 114 gene clusters, demonstrating that A. hancockii has the capacity to degrade cellulose, hemicellulose, lignin, pectin, starch, chitin, cutin and fructan as nutrient sources. Like most Aspergillus species, A. hancockii exhibited a diverse secondary metabolite gene profile, encoding 26 polyketide synthase, 16 nonribosomal peptide synthase and 15 nonribosomal peptide synthase-like enzymes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381763PMC
August 2017

Enantiodivergence in the Biosynthesis of Bromotyrosine Alkaloids from Sponges?

J Nat Prod 2017 01 13;80(1):215-219. Epub 2017 Jan 13.

Department of Chemistry and Biomolecular Sciences, Macquarie University , Sydney, NSW 2109, Australia.

The isolation of bromotyrosine alkaloids, some of which are enantiomers of previously isolated compounds, has highlighted a possible enantiodivergence 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.6b01038DOI Listing
January 2017

Aspergillus Sydowii Marine Fungal Bloom in Australian Coastal Waters, Its Metabolites and Potential Impact on Symbiodinium Dinoflagellates.

Mar Drugs 2016 Mar 16;14(3). Epub 2016 Mar 16.

Institute for Marine & Antarctic Studies, University of Tasmania, Hobart, Tasmania 7004, Australia.

Dust has been widely recognised as an important source of nutrients in the marine environment and as a vector for transporting pathogenic microorganisms. Disturbingly, in the wake of a dust storm event along the eastern Australian coast line in 2009, the Continuous Plankton Recorder collected masses of fungal spores and mycelia (~150,000 spores/m³) forming a floating raft that covered a coastal area equivalent to 25 times the surface of England. Cultured A. sydowii strains exhibited varying metabolite profiles, but all produced sydonic acid, a chemotaxonomic marker for A. sydowii. The Australian marine fungal strains share major metabolites and display comparable metabolic diversity to Australian terrestrial strains and to strains pathogenic to Caribbean coral. Secondary colonisation of the rafts by other fungi, including strains of Cladosporium, Penicillium and other Aspergillus species with distinct secondary metabolite profiles, was also encountered. Our bioassays revealed that the dust-derived marine fungal extracts and known A. sydowii metabolites such as sydowic acid, sydowinol and sydowinin A adversely affect photophysiological performance (Fv/Fm) of the coral reef dinoflagellate endosymbiont Symbiodinium. Different Symbiodinium clades exhibited varying sensitivities, mimicking sensitivity to coral bleaching phenomena. The detection of such large amounts of A. sydowii following this dust storm event has potential implications for the health of coral environments such as the Great Barrier Reef.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md14030059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810073PMC
March 2016

Identifying the cellular targets of natural products using T7 phage display.

Nat Prod Rep 2016 05;33(5):626-36

Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW 2109, Australia.

Covering: up to the end of 2015While Nature continues to deliver a myriad of potent and structurally diverse biologically active small molecules, the cellular targets and modes of action of these natural products are rarely identified, significantly hindering their development as new chemotherapeutic agents. This article provides an introductory tutorial on the use of T7 phage display as a tool to rapidly identify the cellular targets of natural products and is aimed specifically at natural products chemists who may have only limited experience in molecular biology. A brief overview of T7 phage display is provided, including its strengths, weaknesses, and the type of problems that can and cannot be tackled with this technology. Affinity probe construction is reviewed, including linker design and natural product derivatisation strategies. A detailed description of the T7 phage biopanning procedure is provided, with valuable tips for optimising each step in the process, as well as advice for identifying and avoiding the most commonly encountered challenges and pitfalls along the way. Finally, a brief discussion is provided on techniques for validating the cellular targets identified using T7 phage display.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c5np00128eDOI Listing
May 2016

Aranciamycins I and J, Antimycobacterial Anthracyclines from an Australian Marine-Derived Streptomyces sp.

J Nat Prod 2015 Apr 19;78(4):949-52. Epub 2015 Mar 19.

†Institute for Molecular Bioscience, ⊥Diamantina Institute, and ∥Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, QLD 4072, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.5b00095DOI Listing
April 2015

Shornephine A: structure, chemical stability, and P-glycoprotein inhibitory properties of a rare diketomorpholine from an Australian marine-derived Aspergillus sp.

J Org Chem 2014 Sep 2;79(18):8700-5. Epub 2014 Sep 2.

Institute for Molecular Bioscience, The University of Queensland , St. Lucia, QLD 4072, Australia.

Chemical analysis of an Australian marine sediment-derived Aspergillus sp. (CMB-M081F) yielded the new diketomorpholine (DKM) shornephine A (1) together with two known and one new diketopiperazine (DKP), 15b-β-hydroxy-5-N-acetyladreemin (2), 5-N-acetyladreemin (3), and 15b-β-methoxy-5-N-acetyladreemin (4), respectively. Structure elucidation of 1-4 was achieved by detailed spectroscopic analysis, supported by chemical degradation and derivatization, and biosynthetic considerations. The DKM (1) underwent a facile (auto) acid-mediated methanolysis to yield seco-shornephine A methyl ester (1a). Our mechanistic explanation of this transformation prompted us to demonstrate that the acid-labile and solvolytically unstable DKM scaffold can be stabilized by N-alkylation. Furthermore, we demonstrate that at 20 μM shornephine A (1) is a noncytotoxic inhibitor of P-glycoprotein-mediated drug efflux in multidrug-resistant human colon cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo501501zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168782PMC
September 2014
-->