Australian Marine and Terrestrial Streptomyces-Derived Surugamides, and Synthetic Analogs, and Their Ability to Inhibit Dirofilaria immitis (Heartworm) Motility.

A bioassay-guided chemical investigation of a bacterium, Streptomyces sp. CMB-MRB032, isolated from sheep feces collected near Bathurst, Victoria, Australia, yielded the known polyketide antimycins A4a (1) and A2a (2) as potent inhibitors of Dirofilaria immitis (heartworm) microfilaria (mf) motility (EC50 0.0013-0.0021 µg/mL), along with the octapeptide surugamide A (3) and the new N-methylated analog surugamide K (4). With biological data suggesting surugamides may also exhibit activity against D. immitis, a GNPS molecular network analysis of a library of microbes sourced from geographically diverse Australian ecosystems identified a further five taxonomically and chemically distinct surugamide producers. Scaled-up cultivation of one such producer, Streptomyces sp. CMB-M0112 isolated from a marine sediment collected at Shorncliff, Qld, Australia, yielded 3 along with the new acyl-surugamides A1-A4 (5-8). Solid-phase peptide synthesis provided additional synthetic analogs, surugamides S1-S3 (9-11), while derivatization of 3 returned the semi-synthetic surugamide S4 (12) and acyl-surugamides AS1-AS3 (13-15). The natural acyl-surugamide A3 (7) and semi-synthetic acyl-surugamide AS3 (15) were shown to selectively inhibit D. immitis mf motility (EC50 3.3-3.4 µg/mL), however, unlike antimycins 1 and 2, were inactive against the gastrointestinal nematode Haemonchus contortus L1-L3 larvae (EC50 > 25 µg/mL) and were not cytotoxic to mammalian cells (human colorectal carcinoma SW620, IC50 > 30 µg/mL). A structure-activity relationship (SAR) study on the surugamides 3-15 revealed that selective acylation of the Lys3-ε-NH2 correlates with anthelmintic activity.

Glyclauxins A-E: Dimeric Oxaphenalenone Aminoglycosides from an Australian Wasp Nest-Derived Fungus Talaromyces sp. CMB-MW102.

Chemical analysis of cultures of a Queensland mud dauber wasp nest-derived fungus, Talaromyces sp. CMB-MW102, yielded the known dimeric oxaphenalenone duclauxin (1) along with a family of new 1-deoxy-d-glucosamine adducts, glyclauxins A-E (2-6). Despite 1D NMR spectra of 2-6 being compromised by broadening of selected resonances, structures inclusive of absolute configuration were assigned on the basis of detailed spectroscopic analysis and biogenetic considerations, as well as biomimetic semisynthesis and chemical interconversion. For example, exposure of duclauxin (1) to synthetic 1-deoxy-d-glucosamine yielded glyclauxin B (3), while on handling and storage, glyclauxins C (4) and D (5) (bearing a 7-OMe moiety) proved chemically labile and underwent quantitative transformation to glyclauxins B (3) and A (2), respectively. These latter observations on chemical reactivity and stability informed a proposed biogenetic relationship linking all known members of the extended duclauxin family. Notwithstanding their potential status as artifacts, the detection of glyclauxins B (3) and A (2) in a fresh CMB-MW102 culture extract confirmed their natural product status.

Talarolides Revisited: Cyclic Heptapeptides from an Australian Marine Tunicate-Associated Fungus, Talaromyces sp. CMB-TU011.

Application of a miniaturized 24-well plate system for cultivation profiling (MATRIX) permitted optimization of the cultivation conditions for the marine-derived fungus Talaromyces sp. CMB-TU011, facilitating access to the rare cycloheptapeptide talarolide A (1) along with three new analogues, B-D (2-4). Detailed spectroscopic analysis supported by Marfey's analysis methodology was refined to resolve N-Me-l-Ala from N-Me-d-Ala, l-allo-Ile from l-Ile and l-Leu, and partial and total syntheses of 2, and permitted unambiguous assignment of structures for 1 (revised) and 2-4. Consideration of diagnostic ROESY correlations for the hydroxamates 1 and 3-4, and a calculated solution structure for 1, revealed how cross-ring H-bonding to the hydroxamate moiety influences (defines/stabilizes) the cyclic peptide conformation. Such knowledge draws attention to the prospect that hydroxamates may be used as molecular bridges to access new cyclic peptide conformations, offering the prospect of new biological properties, including enhanced oral bioavailability.

Phoslactomycins Revisited: Polyketide Tetrahydrofurans and Lactones from an Australian Wasp Nest-Derived Streptomyces sp. CMB-MW079.

Molecular network analysis of Streptomyces sp. CMB-MW079 detected rare phosphorylated natural products. Miniaturized cultivation profiling (MATRIX) established optimal conditions for the production, isolation, and identification of the polyketide δ-lactone phoslactomycin E (1) and new ester homologues, phoslactomycins J and K (2 and 3), as well as unprecedented heterocyclic analogues, the tetrahydrofuran cyclolactomycins A-D (4-7) and γ-lactone isocyclolactomycins A-C (8-10). We propose a biogenetic relationship linking these cometabolites with the known lactomycins A-C which were tentatively identified as minor cometabolites.

Exploring Natural Product Artifacts: The Polyketide Enterocin Warms to a Ballet of Isomers.

The polyketide enterocin is responsive to environmental stimuli, where mild heating promotes an equilibrium mixture of the isomeric acetals enterocins B and C, which subsequently undergo pseudo-chair-boat inversion to enterocin D. When exposed to aqueous base, enterocin is converted to the isomeric Michael acceptor enterocin F. These studies demonstrate that knowledge of environmental stimuli and associated artifacts is critical to understanding the chemical and ecological properties of enterocins and other classes of natural products.