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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.

Chemical investigation of Australian pasture plant-derived Streptomyces sp. CMB-PB041, supported by miniaturized cultivation profiling and molecular network analysis, led to the isolation and characterization of 13 new macrocyclic spirotetronates, glenthmycins A-M ( 1 - 13 ), with structures assigned by detailed spectroscopic analysis, chemical degradation and derivatization, and mechanistic and biosynthetic considerations. Hydrolysis of glenthmycin B ( 2 ) yielded the aglycone 14 , whose structure and absolute configuration were secured by X-ray analysis, along with the unexpected amino sugar residues glenthose lactams A ( 15 ) and B ( 16 ), with Mosher analysis of 15 facilitating assignment of absolute configurations of the amino sugar. While the glenthmycins proved to be acid stable, treatment of isomeric glenthmycins (i.e., 3 , 6 , and 8 ) with base catalyzed rapid intramolecular trans -esterification to regio-isomeric mixtures (i.e., 3 + 6 + 8 ). Exposure of 5 to base achieved the same intramolecular trans -esterification and was instrumental in detecting and tentatively identifying two additional minor co-metabolites, glenthmycins N ( 19 ) and O ( 20 ). A structure-activity relationship analysis carried out on 1 - 13 and the semisynthetic analogues 14 and 21 - 26 revealed a promising Gram +ve antibacterial pharmacophore, effective against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), but with no detectable cytotoxicity to eukaryotic cells (i.e., fungal and human carcinoma). Of particular note, the semisynthetic analogue glenthmycin K 9-valerate ( 26 ) was unique among glenthmycins in potently inhibiting growth of the full panel of Gram +ve pathogens (IC 50 0.2-1.6 μM). We conclude with an observation that any future evaluation of the antibacterial potential of glenthmycins and related macrocyclic spirotetronates may do well to include important soil-derived Gram +ve pathogens, such as Bacillus anthrax , Clostridium botulinum , and Rhodococcus equi , the causative agents of anthrax, botulism, and livestock pneumonia.

The Australian plant pasture-derived Streptomyces sp. CMB-PB042 yielded the unprecedented polycyclic C -aminoglycoside-pyranonaphthoquinone polyketides glenthamine A ( 1 ) and glenthimine A ( 2 ), the latter being a rare example of a naturally occurring imine, along with the spiropolyketide glenthol A ( 3 ), its hydrolysis artifact glenthol B ( 4 ), and the highly rearranged C -aminoglycoside-pyranonaphthoquinone glenthamide A ( 5 ). Structures including absolute configurations of 1 - 5 were assigned by spectroscopic analysis, chemical interconversion, and biosynthetic considerations.

Using a molecular networking guided strategy, chemical analysis of the Australian mullet fish gastrointestinal tract-derived fungus Amauroascus sp. CMB-F713 yielded a family of polyketide pyrones, amaurones A-I ( 1 - 9 ), featuring an unprecedented carbon skeleton. Structures were assigned to 1 - 9 by detailed spectroscopic analysis (including X-ray analysis of 1 ), biosynthetic considerations, and chemical interconversions. For example, the orthoacetate 5 was unstable when stored dry at room temperature, transforming to the monoacetates 2 and 3 , while mild heating (40 °C) prompted quantitative conversion of 3 to 2 , via an intramolecular trans -acetylation. Likewise, during handling, the monoacetate 1 was prone to intramolecular trans -acetylation, leading to an equilibrium mixture with the isomeric monoacetate amaurone J ( 10 ), confirmed when partial hydrolysis of the diacetate 2 yielded the monoacetates 1 and 10 and the triol amaurone K ( 11 ).

A southern Australian soil isolate, Amycolatopsis sp. MST-108494, was subjected to a panel of fermentation and media optimization trials, supported by analytical chemical profiling, to detect and enhance production of a rare class of secondary metabolites. Chemical fractionation of two complementary fermentations yielded three new polyketides, identified by detailed spectroscopic analysis as the glycosylated macrolactones, amycolatopsins A (1), B (2) and C (3), closely related to the ammocidins and apoptolidins. Amycolatopsins 1 and 3 selectively inhibited growth of Mycobacterium bovis (BCG) and Mycobacterium tuberculosis (H37Rv) when compared with other Gram-positive or Gram-negative bacteria, with 3 exhibiting low levels of cytotoxicity toward mammalian cells. Thus, our data reveal promising structure activity relationship correlations where the antimycobacterial properties of amycolatopsins are enhanced by hydroxylation of the 6-Me (that is, 1 and 3), whereas mammalian cytotoxicity is decreased by hydrolysis of the disaccharide moiety (that is, 3).

Cultures of the estuarine fungus Penicillium roseopurpureum (CMB-MF038) yielded a diverse array of polyketides, many of which were related via a highly convergent biosynthetic pathway. In addition to revising and assigning structures, and documenting chemical and biological properties, pro-drug cytotoxic properties were attributed to roseopurpurins H (10) and I (11) on the basis of in situ reverse Michael addition to a cytotoxic Michael acceptor (12).

Chemical investigations of a soil-derived Streptomyces sp. led to the isolation of five new polyketides, (+)-oxanthromicin, (±)-hemi-oxanthromicins A/B, (±)-spiro-oxanthromicin A and oxanthroquinone, and the known alkaloid staurosporine, and the detection of four new metastable analogues, (±)-spiro-oxanthromicins B1/B2/C1/C2. Among the compounds tested, SAR investigations established that the synthetic oxanthroquinone ethyl ester and 3-O-methyl-oxanthroquinone ethyl ester were optimal at mislocalising oncogenic mutant K-Ras from the plasma membrane of intact Madin-Darby canine kidney (MDCK) cells (IC50 4.6 and 1.2 μM), while a sub-EC50 dose of (±)-spiro-oxanthromicin A was optimal at potentiating (750%) the K-Ras inhibitory activity of staurosporine (IC50 60 pM). These studies demonstrate that a rare class of Streptomyces polyketide modulates K-Ras plasma membrane localisation, with implications for the future treatment of K-Ras dependent cancers.

Cultures of the estuarine fungus Penicillium roseopurpureum (CMB-MF038) yielded a diverse array of polyketides, many of which were related via a highly convergent biosynthetic pathway. In addition to revising and assigning structures, and documenting chemical and biological properties, pro-drug cytotoxic properties were attributed to roseopurpurins H (10) and I (11) on the basis of in situ reverse Michael addition to a cytotoxic Michael acceptor (12). [ABSTRACT FROM AUTHOR]