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Activation of a cryptic polyketide synthase gene cluster hkn from Aspergillus hancockii via overexpression of the gene-cluster-specific transcription factor HknR led to the discovery of a novel polycyclic metabolite, which we named hancockinone A. The compound features an unprecedented prenylated 6/6/6/5 tetracarbocyclic skeleton and shows moderate antibacterial activity. Heterologous expression, substrate feeding, and in vitro assays confirmed the role of cytochrome P450 HknE in constructing the five-membered ring in hancockinone A from the precursor neosartoricin B.

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.

Activation of a cryptic polyketide synthase gene cluster

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.

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.

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.

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.

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 examples 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.

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-Guerin (BCG), suggestive of a new mechanism of action that could inform the development of next-generation antitubercular drugs.