Nonenzymatic Sequestering of Formaldehyde into the Antibiotic Methylene-Bridged Dimer Phaeochromycin F by Streptomyces sp. OUCMDZ-4982 as a Possible Multipronged Chemical Defense Mechanism.

Metabolites with high chemical reactivity serve important roles in chemical defenses of organisms. Formaldehyde, as a simple and highly reactive small molecule, can be produced by microorganisms, plants, and animals. Its toxicity is well known, but information about its other biological functions remains scarce. Here, we report that the natural product SEK34b produced by Streptomyces species can react nonenzymatically with formaldehyde in water to yield the methylene-bridged dimer phaeochromycin F. This process can eliminate the toxic substance formaldehyde produced by Staphylococcus aureus. Furthermore, there is a substantial inhibitory impact of phaeochromycin F on S. aureus. We hypothesize that these constitute an integrated system of defense and attack of Streptomyces species against competitors. Our study indicates that formaldehyde can react with vancomycin and tigecycline under mild conditions to generate the derivatives bearing an imidazolidin-4-one moiety, thereby reducing the antibacterial activity of these antibiotics. These data provide a possible chemical interaction mechanism of bacteria involving the nonenzymatic reactions of formaldehyde with highly reactive natural products.

Methylene-bridged dimeric natural products involving one-carbon unit in biosynthesis.

Covering: up to February 2022Naturally occurring dimeric molecules attract considerable attention from both chemists and biologists. The methylene-bridged dimers with one-carbon (C1) unit in biosynthesis, which are a small class of structurally diverse natural products, are found in plants, microorganisms, and marine bryozoan. Some individual dimers showed more significant biological activities than the corresponding monomers. Focusing on these dimers with a methylene linker, we here reviewed associated progress in the isolation, biological activity, chemical synthesis, and the proposed dimerization mechanism. The structural characteristics of the monomeric substrates are summarized, which indicated that most of these dimers might be formed through nonenzymatic dimerization involving a strong electrophilic C1 unit such as formaldehyde. This kind of dimerization is an effective synthetic strategy for the discovery of new biologically active compounds.

Aromatic Polyketides and Hydroxamate Siderophores from a Marine-Algae-Derived Streptomyces Species.

Four new aromatic polyketides, wailupemycins M-P (1-4), and two new hydroxamate siderophores, streptamides A (5) and B (6), together with the previously reported nocardamine (7), were isolated from the marine-algae-derived Streptomyces sp. OUCMDZ-3434. Wailupemycins M-P (1-4), possessing an α-pyrone moiety, were isolated from the extract of a liquid fermentation, and the siderophores (5-7) were isolated from the extract of a solid fermentation. Their structures were assigned based on detailed spectroscopic analysis and quantum chemical calculations. Compounds 5-7 were capable of binding Fe(III). Compound 5 can form a tighter Fe(III) complex than that of deferoxamine B mesylate (DFB).

Expanding the Chemical Diversity of Secondary Metabolites Produced by Two Marine-Derived Enterocin- and Wailupemycin-Producing Streptomyces Strains.

To expand the chemical diversity of secondary metabolites produced by two marine-derived enterocin- and wailupemycin-producing Streptomyces strains, OUCMDZ-3434 and OUCMDZ-2599, precursor feeding and solid fermentation strategies were used. Two new compounds, wailupemycins Q (1) and R (2), were isolated from the extracts of liquid and solid fermentation of OUCMDZ-3434. Furthermore, during the fermentation of OUCMDZ-3434, p-fluorobenzoic acid was added as the key biosynthetic precursor, which resulted in the isolation of eight new fluorinated enterocin and wailupemycin derivatives (3-10) and 10 previously reported analogues (11-20). From the solid fermentation extract of OUCMDZ-2599, a new sulfur-containing compound thiotetromycin B (21) and its known analogue thiotetromycin (22) were identified. Moreover, the solid fermentation strategy effectively activated the biosynthesis of siderophores (23-25) of strain OUCMDZ-2599. Compound 3 showed moderate antibacterial activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus subsp. aureus with MIC values of 4 µg/mL. Compounds 23-25 were significantly capable of binding Fe(III).