The siderophore myxochelin A is a potent inhibitor of human 5-lipoxygenase (5-LO). To clarify whether the iron-chelating properties of myxochelin A are responsible for this activity, several analogues of this compound were generated in the native producer Pyxidicoccus fallax by precursor-directed biosynthesis. Testing in a cell-free assay unveiled three derivatives with bioactivity comparable with that of myxochelin A. Furthermore, it became evident that inhibition of 5-LO by myxochelins does not correlate with their iron affinities.
Nitrobenzothiazinones are among the most potent antituberculosis agents. Herein, we disclose an unprecedented in vivo reduction process that affords Meisenheimer complexes of the clinical candidates BTZ043 and PBTZ169. The reduction is reversible, occurs in all mammalian species investigated, has a profound influence on the in vivo ADME characteristics, and has considerable implications for the design and implementation of clinical studies. The reduction was confirmed by chemical studies that enabled the complete characterization of the Meisenheimer complex and its subsequent chemistry. Combination of the in vivo and chemical studies with LC-MS characterization and assay development also provides a basis for rational lead optimization of this very promising class of antituberculosis agents.
Photoreactive siderophores have a major impact on the growth of planktonic organisms. To date, these molecules have mainly been reported from marine bacteria, although evidence is now accumulating that some terrestrial bacteria also harbor the biosynthetic potential for their production. In this paper, we describe the genomics-driven discovery and characterization of variochelins, lipopeptide siderophores from the bacterium Variovorax boronicumulans, which thrives in soil and freshwater habitats. Variochelins are different from most other lipopeptide siderophores in that their biosynthesis involves a polyketide synthase. We demonstrate that the ferric iron complex of variochelin A possesses photoreactive properties and present the MS-derived structures of two degradation products that emerge upon light exposure.
Ralsolamycin, an inducer of chlamydospore formation in fungi, was recently reported from the plant pathogenic bacterium Ralstonia solanacearum. Although interpretation of tandem mass data and bioinformatics enabled a preliminary chemical characterization, the full structure of ralsolamycin was not resolved. We now report the recovery of this secondary metabolite from an engineered R. solanacearum strain. The structure of ralsolamycin was elucidated by extensive spectroscopic analyses. Chemical derivatization as well as bioinformatics were used to assign the absolute stereochemistry. Our results identified an erroneous genome sequence, thereby emphasizing the value of chemical methods to complement bioinformatics-based procedures in natural product research.
The gulmirecins constitute a new class of glycosylated macrolides that were isolated from the predatory bacterium Pyxidicoccus fallax HKI 727. Their structures were solved by a combination of NMR spectroscopic experiments and chemical derivatization. Analysis of the annotated gulmirecin gene cluster complemented the configurational assignment and provided insights into the stereochemical course of the biosynthetic assembly. The gulmirecins exhibit strong activity against staphylococci, including methicillin-resistant Staphylococcus aureus, but no cytotoxic effects on human cells.
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