PHARMACEUTICAL BIODISCOVERY - Can be defined as the search for bioactive natural products that inform and inspire the development of new human therapeutics (drugs), to improve and replace those that have become less effective, and to bring to the community safe and effective treatments for an ever-wider array of diseases.
Historically the pharmaceutical industry has relied heavily on natural products, particularly microbial natural products, which represent an extraordinarily diverse, pre-assembled pool of biologically active molecules, programmed by evolution to be potent and selective modulators of key biopolymers, cells, tissues, organs, and living systems. The actinomyces, for example, are the source of >50% of antibiotics in use today, including macrolides (e.g. erythromycin), glycopeptides (e.g. vancomycin), aminoglycosides (e.g. streptomycin), anthracyclins (e.g. tetracycline) and polyenes (e.g. amphotericin), as well as anticancer agents (e.g. doxorubicin), immuno-suppressives (e.g. rapamycin), anthelmintics (e.g. ivermectin) and insecticides (e.g. spinosyns). Likewise, fungi have been significant performers, with the genus Penicillium delivering one of the most recognized drug class in modern medicine, the antibiotic penicillins, and one of the most commercially successful, the anti-lipidemic statins.
The journey to detect, isolate, identify, evaluate, develop, manufacture and market natural products sparked and fuelled a revolution in global science. Notwithstanding past successes, there is a compelling need to discover better pharmaceuticals.
Our pharmaceutical biodiscovery research is a logical extension of our expertise in marine and microbial biodiscovery. To support our efforts we employ in-house bioassays to target;
To further extend the scope of our research we work closely with collaborating labs to access assays against a range of molecular targets and indications, including;
While it should come as no surprise that our most exciting Pharmaceutical Biodiscovery discoveries remain commercial-in-confidence, outlined below a several examples of our published achievements.
(see Banner Images for chemical structures)
INFECTIOUS DISEASE - TUBERCULOSIS
Abyssomicin J – A dimeric thioether polyketide and a rare example of a natural pro-drug, abyssomicin J was produced by a strain of bacteria isolated from a South China Sea deep-sea sediment. On treating Mycobacterium tuberculosis (Mtb) with abyssomicin J, the thioether bridge underwent rapid enzyme-mediated oxidative activation, triggering an unprecedented in situ quadruple reverse Michael addition cascade to yield the antitubercular agent atrop-abyssomicin C. Knowledge of the absyssomicin J pharmacophore has implications for the effective masking of other Michael acceptor based therapeutics, including new antitubercular drugs.
(Angew Chem Int Ed, 2013, 52, 1231-1234)
Wollamides – Cyclic hexapeptides produced by a strain of bacteria isolated from arid soil collected from a remote North Queensland cattle station, the wollamides are non-toxic to mammalian cells, and exceptionally potent antitubercular agents. The wollamides are effective against drug sensitive and MDR strains of Mycobacterium tuberculosis (Mtb), and clear intracellular macrophage infections. Re-engineering of the wollamide antitubercular pharmacophore is a work-in-progress.
(Org Lett, 2014, 16, 5120-5123)
INFECTIOUS DISEASE - BACTERIA
Viridicatumtoxins – Rare examples of tetracycline-like polyketide anthraquinones produced by a fungus from the inner tissues of a mollusk collected in the Brisbane intertidal zone, viridicatumtoxin B is an exceptionally potent antibacterial against vancomycin resistant Enterococci (VRE). Structure activity relationship investigations (by co-metabolite) indicated that viridicatumtoxin-inspired antibiotics have the potential to be superior to commercial tetracycline antibiotics.
(J Org Chem, 2015, 80, 12501-12508)
INFECTIOUS DISEASE - FUNGI
Reveromycins – Polyketide spiroketals produced by marine-derived and terrestrial Streptomyces spp (MST-MA568 and MST-RA7781), featuring a rare hemi-succinate:ketal-succinyl equilibrium, and anti fungal properties.
(Org & Biomol Chem, 2011, 9, 1201-1211)
INFECTIOUS DISEASE - MALARIA
Mollemycin A – A first-in-class glyco-hexadepsipeptide-polyketide produced by a strain of bacteria isolated from marine sediments collected near South Molle Island, Queensland, mollemycin A is an exceptionally potent antimalarial effective against both drug sensitive and drug resistant Plasmodium falciparum. detection and characterisation of the mollemycin biosynthetic gene cluster is a work-in-progress, with a view to improving access to the mollemycin scaffold, to support structure activity relationship investigations.
(Org Lett, 2014, 16, 1716-1719)
Trachycladindoles – A first-in-class family of indole-2-carboxylate 2-amino-4,5-dihydroimidazole alkaloids isolated from a marine sponge, Trachycladus laevispirulifer, collected from commercial trawler by-catch in the Great Australian Bight, the trachycladindoles exhibit promising aniticancer properties, and are exceptionally potent kinase GSK3-beta inhibitors. Knowledge of the trachycladindole pharmacophore has the potential to inform the development of new treatments for neurodegenerative diseases (i.e. Alzheimer’s disease).
(Org & Biomol Chem, 2008, 6, 2765-2771)
Ningalins – Rare examples of pyrrolo-polyphenols, ningalins (and co-metabolite lamellarins) were isolated from a marine tunicate, Didemnum sp., collected during scientific trawling operations off the northern Rottenest Shelf, Western Australia. Selected ningalins (i.e. C, D and G) are potent kinases CK1-delta, CDK5 and GSK3-beta inhibitors. Knowledge of the ningalin pharmacophore has the potential to inform the development of new treatments for neurodegenerative diseases (i.e. Alzheimer’s disease).
Kibdelones – Polycyclic polyketide quinones produced by a strain of bacterial isolated from soil collected from a timber woolshed near Port Augusta, South Australia, the kibelones exhibit potent anticancer properties, and their chemistry is characterized by a remarkable Redox-mediated plasticity.
(Chem Eur J, 2007, 13, 1610-1619)
Oxanthomicins – A family of polyketide anthraquinones produced by two strains of bacteria isolated from arid soil samples collected from remote and regional New South Wales, Australia, natural and synthetic oxanthromicins are potent K-Ras plasma membrane (PM) localisation inhibitors. When localized to the plasma membrane, K-Ras is a key driver of pancreatic, colon and non-small cell lung cancers – all refractive to modern cancer chemotherapies. Although inhibition of K-Ras PM localization is known to block all oncogenic activity, clinically useful inhibitors have proved elusive. Knowledge of the oxanthromicin pharmacophore has the potential to inform the development of new K-Ras anticancer drugs cable of treating intractable cancers.
(Org & Biomol Chem, 2014, 12, 4872-4878)
Shornephine A – A rare example of a diketomorpholine alkaloid produced by a strain of bacteria isolated from a marine-sediment sample collected in shallow water off Shornecliff, Queensland. Shornephine A possesses a highly “primed” molecular scaffold which undergoes a rapid acid-mediated rearrangement to a highly activated seco-shornephine intermediate, that is a potent P-gp inhibitor. Knowledge of shornephine pharmacophore has the potential to inform the development of clinically useful P-gp anticancer agents capable of treating MDR cancers.
(J Org Chem, 2014, 79, 8700-8705)
CHRONIC INFLAMMATORY PAIN
Ircinianin lactams – Rare examples of sesterterpene glycinyl-lactams isolated from several marine sponges of the genus Psammocinia collected by SCUBA from inshore waters along the Victorian and New South Wales coasts. Selected members of this structure class exhibit potent and isoform selective potentiation of glycine gated chloride channel receptors (GlyR). Knowledge of the ircinianin lactic pharmacophore has the potential to inform the development of first-in-class analgesics for the treatment of chronic inflammatory pain.
(Org & Biomol Chem, 2013, 11, 4695-4701)
OBESITY, DIABETES & ATHEROSCLEROSIS
Heterofibrins – Rare examples of diyne-ene fatty acids, the heterofibrins are the first known examples of natural monolactyl and dilactyl lipid esters. Isolated from a marine sponge, Heterofibria sp., collected during scientific trawling operations in the Great Australian Bight, the heterofibrins are non-cytotoxic inhibitors of intracellular lipid droplet formation. Knowledge of the heterofibrin pharmacophore has the potential to inform the development of new drugs to treat obesity, diabetes and atherosclerosis.