Abstract:A new chlorinated metabolite designated chlokamycin (1), was isolated along with ikarugamycin (2) from the culture broth of the marine-derived Streptomyces sp. MA2-12. The structure of 1 was elucidated based on spectroscopic analyses (1D and 2D NMR data and ROESY correlations). Chlokamycin moderately inhibited the growth of Jurkat cells and HCT116 cells with IC 50 values of 24.7 and 33.5 M, respectively.
“…Accordingly, we used a phylogenyguided degenerate oligonucleotide design strategy (see Methods, Table S3) and the resulting primers were validated against a panel of PTM + bacteria having diverse FtdB sequences (Fig S7 We found all tested group 1 strains produced highly similar PTM profiles (Fig 5A, EFG04254.1 was cloned to constitutive-expression vector pJMD3 and tested for its ability to rescue ftdF-dependent mass features in JV180 DftdADftdF (in parallel with a FtdF JV180 control). After analyzing the complemented strains (JV2997 and JV3010, respectively), we found both CYP450 genes were functional in restoring production of 1 However, this cannot completely explain the differences in product profiles; the B-3009 double mutant produces several other PTM-like mass features (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) to obtain these strains were Humic-acid Vitamin (HV), Arginine Glycerol-Salts(AGS),…”
Polycyclic tetramate macrolactams (PTMs) are bioactive natural products commonly associated with certain actinobacterial and proteobacterial lineages. These molecules have been the subject of numerous structure-activity investigations since the 1970s. New members continue to be pursued in wild and engineered bacterial strains, and advances in PTM biosynthesis suggests their outwardly simplistic biosynthetic gene clusters (BGCs) belie unexpected product complexity. Towards addressing the origins of this complexity and understanding its influence on PTM discovery, we engaged in a combination of bioinformatics to systematically classify PTM BGCs, and PTM- targeted metabolomics to compare the products of select BGC types. By comparing groups of producers and BGC mutants, we exposed knowledge gaps that complicate bioinformatics-driven product predictions. In sum, we provide new insights into the evolution of PTM BGCs while systematically accounting for the PTMs discovered thus far. The combined computational and metabologenomic findings presented here should prove useful for guiding future discovery.
“…Accordingly, we used a phylogenyguided degenerate oligonucleotide design strategy (see Methods, Table S3) and the resulting primers were validated against a panel of PTM + bacteria having diverse FtdB sequences (Fig S7 We found all tested group 1 strains produced highly similar PTM profiles (Fig 5A, EFG04254.1 was cloned to constitutive-expression vector pJMD3 and tested for its ability to rescue ftdF-dependent mass features in JV180 DftdADftdF (in parallel with a FtdF JV180 control). After analyzing the complemented strains (JV2997 and JV3010, respectively), we found both CYP450 genes were functional in restoring production of 1 However, this cannot completely explain the differences in product profiles; the B-3009 double mutant produces several other PTM-like mass features (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) to obtain these strains were Humic-acid Vitamin (HV), Arginine Glycerol-Salts(AGS),…”
Polycyclic tetramate macrolactams (PTMs) are bioactive natural products commonly associated with certain actinobacterial and proteobacterial lineages. These molecules have been the subject of numerous structure-activity investigations since the 1970s. New members continue to be pursued in wild and engineered bacterial strains, and advances in PTM biosynthesis suggests their outwardly simplistic biosynthetic gene clusters (BGCs) belie unexpected product complexity. Towards addressing the origins of this complexity and understanding its influence on PTM discovery, we engaged in a combination of bioinformatics to systematically classify PTM BGCs, and PTM- targeted metabolomics to compare the products of select BGC types. By comparing groups of producers and BGC mutants, we exposed knowledge gaps that complicate bioinformatics-driven product predictions. In sum, we provide new insights into the evolution of PTM BGCs while systematically accounting for the PTMs discovered thus far. The combined computational and metabologenomic findings presented here should prove useful for guiding future discovery.
Comprehensive Summary
Natural products derived from marine microorganisms have been received great attention as a potential source of new compound entities for drug discovery. The unique marine environment brings us a large group of halogen‐containing natural products with abundant biological functionality and good drugability. Meanwhile, biosynthetically halogenated reactions are known as a significant strategy used to increase the pharmacological activities and pharmacokinetic properties of compounds. Given that a tremendous increase in the number of new halogenated compounds from marine microorganisms in the last five years, it is necessary to summarize these compounds with their diverse structures and promising bioactivities. In this review, we have summarized the chemistry, biosynthesis (related halogenases), and biological activity of a total of 316 naturally halogenated compounds from marine microorganisms covering the period of 2015 to May 2021. Those reviewed chlorinated and brominated compounds with the ratio of 9 : 1 were predominantly originated from 36 genera of fungi (62%) and 9 bacterial strains (38%) with cytotoxic, antibacterial, and enzyme inhibitory activities, structural types of which are polyketides (38%), alkaloids (27%), phenols (11%), and others. This review would provide a plenty variety of promising lead halogenated compounds for drug discovery and inspire the development of new pharmaceutical agents.
“…Ikarugamycins 109, 111, 113, and clifednamide A(114), were re-discovered from a marine sponge-associated novel actinomycete Streptomyces zhaozhouensis (strain MCCB267) using a cytotoxicity-guided strategy[108]. All compounds(109,111,113, and 114) displayed promising cytotoxic activity against NCI-H460 lung carcinoma cells (IC 50 = 1.43-16.26 µg/mL) by binding with DNA and disrupting the cell cycle to induce apoptotic stimuli leading to cell death in the G1 or S phase[108].Capsimycin(115), bearing an O-methoxy group at the C-30 of ikarugamycin epoxide(116), was first reported as an antifungal agent from Streptomyces sp. C49-87 in 1979[115].…”
mentioning
confidence: 99%
“…C49-87 in 1979[115]. In 2003, ikarugamycin epoxide (later termed capsimycin B)(116), along with 109, were discovered from Streptomyces sp. Tü 6239[105] and showed moderate antibacterial activity and cytotoxicity[105,110].…”
Tetramic acid (pyrrolidine-2,4-dione) compounds, isolated from a variety of marine and terrestrial organisms, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities. In the past decade, marine-derived microorganisms have become great repositories of novel tetramic acids. Here, we discuss the biological activities of 277 tetramic acids of eight classifications (simple 3-acyl tetramic acids, 3-oligoenoyltetramic acids, 3-decalinoyltetramic acid, 3-spirotetramic acids, macrocyclic tetramic acids, N-acylated tetramic acids, α-cyclopiazonic acid-type tetramic acids, and other tetramic acids) from marine-derived microbes, including fungi, actinobacteria, bacteria, and cyanobacteria, as reported in 195 research studies up to 2019.
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