MICROBIAL BIODISCOVERY - Can be defined as the chemical exploration of bacterial and fungal biodiversity, to detect, isolate, characterize, identify and evaluate structurally diverse natural products.
Over the last two decades the Capon Group has established itself as a leader in the field of microbial biodiscovery. To support our research we assembled a network of UQ, Australian and international collaborators, acquired microbial diversity libraries, and implemented an array of innovative high throughput (HTP) microbial cultivation and chemical profiling methodologies, as summarized below;
Microbial Biodiversity: Genetically diverse microbial isolate libraries, including the Australian Collection of Microbes (>5,000 strains), assembled over a period of >60 years by the UQ School of Microbiology, as well as purpose-built terrestrial (>1,000), marine (>4,000 isolates), venomous animal (>1,000 isolates) and gut/faecal (>1,000) microbe libraries.
HTP Microbial Cultivations: Optimized and implemented a quantitative high throughput (HTP) microbioreactor cultivation system, supportive of multiple media and culture configurations (solid, shaken and static broth). This system permits rapid, reproducible and simultaneous 1.5 mL/1 g cultivations in 24-well plate configurations, generating many hundreds of extracts/week. With in situ solvent extraction this microbioreactor approach enables the rapid interrogation of extracts rich in secondary metabolites.
HTP Chemical Profiling: Our microbioreactor system when coupled with UPLC-DAD and HPLC-MS technology, represents a rapid and cost effective method for qualitative and quantitative analysis of chemical diversity. Chemical profiling can be used to compare isolates, and assess the response of individual isolates to different cultivation conditions, including transcriptional activation by natural chemical cues.
In addition to isolating novel microbial natural products, many featuring complex and unique molecular structures, our research extends to the chemical synthesis and an exploration of the biosynthesis of high priority scaffolds, and investigations into silent biosynthetic gene clusters (see Chemical Ecology).
Listed below are several of our noteworthy microbial natural product discoveries.
(see Banner Images for chemical structures)
Heronamycin A – A benzothiazine ansamycin produced as a co-metabolite with herbimycin A by a marine-derived Streptomyces (CMB-M0392) isolated from a sediment sample collected off Heron Island, Queensland.
(Tet Letts, 2012, 53, 1063-1065)
Heronapyrroles – First-in-class farnesylated 2-nitropyrroles produced by a marine-derived Streptomyces (CMB-M0423) isolated from a sediment sample collected off Heron Island, Queensland, exhibiting promising Gram +ve antibacterial properties.
(Org Lett, 2014, 16, 378-381)
Heronamides – Rare polyketide macrolactams produced by a marine-derived Streptomyces (CMB-M0406) isolated from a sediment sample collected off Heron Island, Queensland. The heronamides are prone to unprecedented oxygen and light catalysed, synchronized tandem cycloadditions.
(Chem Commun, 2016, 52, 6383-6386)
Nocardiopsins – The first examples of macrolide polyketides featuring the rare immuno-suppressant rapamycin /FK506 FKBP12-binding scaffold to be reported in over 30 years, produced by a marine-derived Nocardiopsis sp. (CMB-M0232) isolated from a sediment sample (-55 m) collected off the coast of Brisbane, Australia.
(Tetrahedron, 2013, 69, 692-698)
Nocardioazines – The first example of an isoprene bridged diketopiperazine scaffold, produced by a marine-derived Nocardiopsis sp. (CMB-M0232) isolated from a sediment sample (-55 m) collected off the coast of Brisbane, Australia. Nocardioazine A is a promising inhibitor of the ABC transporter and efflux pump P-glycoprotein, a key determinant in multidrug resistant cancers and infectious diseases.
(Org Lett, 2011, 13, 2770-2773)
Isokibdelones – A family of heterocyclic polyketides produced by a rare Australian soil actinomycete, Kibdelosporangium sp. (MST-108465), featuring a biosynthesis with a unique Baeyer-Villiger like xanthine pirouette rearrangement.
(Org Lett, 2006, 8, 5267-5270)
Rugulotrosins – Dimeric atropisomeric tetrahydroxanthone polyketides produced by Penicillium sp (MST-F8741) isolated from a soil sample collected near Sussex Inlet, New South Wales. The rugulotrosins feature a biosynthesis with exceptional stereochemical fidelity, and exhibit promising Gram +ve antibacterial properties.
(Nature Chemistry, 2015, 7, 234-240)
Aspergillazines – Highly modified dipeptides produced by Aspergillus unilateralis (MST-F8675) isolated from a soil sample collected near Mount Isa, Australia. The aspergillazines feature unprecedented hereto cyclic scaffolds, with highly informative chemical properties.
(Org & Biomol Chem, 2005, 3, 123-129)
Acremolides – Lipodepsipeptides produced by a marine-derived Aspergillus sp. (MST-MF588a) isolated from a sediment sample collected in the Huon River, near Franklin, Tasmania.
(J Nat Prod, 2008, 71, 403-408)
C3 and 2D C3 Marfey’s – A high resolution and high sensitivity methodology for the rapid assignment of absolute configurations to hydrolytically accessible amino acid residues, and to the regiochemistry of enantiomeric amino acid residues, in natural products.
(J Nat Prod, 2016, 79, 421-427)
LPS Stimulation - Methodology for the use of lipopolysaccharide (LPS) from Gram –ve bacteria as a natural chemical cue to simulate fungal silent BGCs. Approximately 10% of fungal cultures treated with LPS (~0.6 ng/mL) are stimulated to enhance and/or accelerate the biosynthesis of transcriptionally active metabolites, and/or activate the transcription of otherwise silent secondary metabolites. LPS mediated stimulation can proceed via a nitric oxide (NO) dependent or independent pathway.