Tuberculosis remains one of the world’s deadliest communicable diseases, novel anti-tuberculosis agents are urgently needed due to severe drug resistance and the co-epidemic of tuberculosis/human immunodeficiency virus. Here, we show the isolation of six anti-mycobacterial ilamycin congeners (1–6) bearing rare L-3-nitro-tyrosine and L-2-amino-4-hexenoic acid structural units from the deep sea-derived Streptomyces atratus SCSIO ZH16. The biosynthesis of the rare L-3-nitrotyrosine and L-2-amino-4-hexenoic acid units as well as three pre-tailoring and two post-tailoring steps are probed in the ilamycin biosynthetic machinery through a series of gene inactivation, precursor chemical complementation, isotope-labeled precursor feeding experiments, as well as structural elucidation of three intermediates (6–8) from the respective mutants. Most impressively, ilamycins E1/E2, which are produced in high titers by a genetically engineered mutant strain, show very potent anti-tuberculosis activity with an minimum inhibitory concentration value ≈9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads.
Four new β-carboline alkaloids, designated marinacarbolines A-D (1-4), two new indolactam alkaloids, 13-N-demethyl-methylpendolmycin (5) and methylpendolmycin-14-O-α-glucoside (6), and the three known compounds 1-acetyl-β-carboline (7), methylpendolmycin (8), and pendolmycin (9) were obtained from the fermentation broth of Marinactinospora thermotolerans SCSIO 00652, a new actinomycete belonging to the family Nocardiopsaceae. Their structures were elucidated by extensive MS and 1D and 2D NMR spectroscopic data analyses. The structure of compound 1 was further confirmed by single-crystal X-ray crystallography. The new compounds 1-6 were inactive against a panel of eight tumor cell lines (IC50>50 μM) but exhibited antiplasmodial activities against Plasmodium falciparum lines 3D7 and Dd2, with IC50 values ranging from 1.92 to 36.03 μM.
Five new compounds, pinazaphilones A and B (1, 2), two phenolic compounds (4, 5), and penicidone D (6), together with the known Sch 1385568 (3), (±)-penifupyrone (7), 3-O-methylfunicone (8), 5-methylbenzene-1,3-diol (9), and 2,4-dihydroxy-6-methylbenzoic acid (10) were obtained from the culture of the endophytic fungus Penicillium sp. HN29-3B1, which was isolated from a fresh branch of the mangrove plant Cerbera manghas collected from the South China Sea. Their structures were determined by analysis of 1D and 2D NMR and mass spectroscopic data. Structures of compounds 4 and 7 were further confirmed by a single-crystal X-ray diffraction experiment using Cu Kα radiation. The absolute configurations of compounds 1-3 were assigned by quantum chemical calculations of the electronic circular dichroic spectra. Compounds 2, 3, 5, and 7 inhibited α-glucosidase with IC50 values of 28.0, 16.6, 2.2, and 14.4 μM, respectively, and are thus more potent than the positive control, acarbose.
Five new C-glycoside angucyclines, named grincamycins B−F (1−5), and a known angucycline antibiotic, grincamycin (6), were isolated from Streptomyces lusitanus SCSIO LR32, an actinomycete of deep sea origin. The structures of these compounds were elucidated on the basis of extensive spectroscopic analyses, including MS and 1D and 2D NMR experiments. All compounds except grincamycin F (5) exhibited in vitro cytotoxicities against the human cancer cell lines HepG2, SW-1990, HeLa, NCI-H460, and MCF-7 and the mouse melanoma cell line B16, with IC 50 values ranging from 1.1 to 31 μM.
Four new norsesquiterpene peroxides, named talaperoxides A-D (1-4), as well as one known analogue, steperoxide B (5, or merulin A), have been isolated from a mangrove endophytic fungus, Talaromyces flavus. Their structures were elucidated mainly by 1D and 2D NMR. Structures of 1, 2, and 5 were further confirmed by single-crystal X-ray diffraction, and their absolute configurations were also determined using copper radiation. Cytotoxic activities of compounds 1-5 were evaluated in vitro against human cancer cell lines MCF-7, MDA-MB-435, HepG2, HeLa, and PC-3. Compounds 2 and 4 showed cytotoxicity against the five human cancer cell lines with IC50 values between 0.70 and 2.78 μg/mL.
It's only natural: The biosynthetic pathway of himastatin from Streptomyces himastatinicus featuring unusual domain organizations is elucidated by genome scanning, generation of in‐frame gene deletion mutants, and complementation experiments. Three cytochrome P450s that catalyze novel post‐tailoring oxidative reactions (see picture) are characterized.
The gene cluster responsible for grincamycin (GCN, 1) biosynthesis in Streptomyces lusitanus SCSIO LR32 was identified; heterologous expression of the GCN cluster in S. coelicolor M512 yielded P-1894B (1b) as a predominant product. The ΔgcnQ mutant accumulates intermediate 1a and two shunt products 2a and 3a bearing L-rhodinose for L-cinerulose A substitutions. In vitro data demonstrated that GcnQ is capable of iteratively tailoring the two L-rhodinose moieties into L-aculose moieties, supporting divergent roles of GcnQ in different hosts.
Griseoviridin (GV) and viridogrisein (VG, also referred to as etamycin), produced by Streptomyces griseoviridis, are two chemically unrelated compounds belonging to the streptogramin family. Both of these natural products demonstrate broad-spectrum antibacterial activity and constitute excellent candidates for future drug development. To elucidate the biosynthetic machinery associated with production of these two unique antibiotics, the gene cluster responsible for both GV and VG production was identified within the Streptomyces griseoviridis genome and characterized, and its function in GV and VG biosynthesis was confirmed by inactivation of 30 genes and complementation experiments. This sgv gene cluster is localized to a 105 kb DNA region that consists of 36 open reading frames (ORFs), including four nonribosomal peptide synthetases (NRPSs) for VG biosynthesis and a set of hybrid polyketide synthases (PKS)-NRPSs with a discrete acyltransferase (AT), SgvQ, to assemble the GV backbone. The enzyme encoding genes for VG versus GV biosynthesis are separated into distinct "halves" of the cluster. A series of four genes: sgvA, sgvB, sgvC, and sgvK, were found downstream of the PKS-NRPS; these likely code for construction of a γ-butyrolactone (GBL)-like molecule. GBLs and the corresponding GBL receptor systems are the highest ranked regulators that are able to coordinate the two streptomyces antibiotic regulatory protein (SARP) family positive regulators SgvR2 and SgvR3; both are key biosynthetic activators. Models of GV, VG, and GBL biosynthesis were proposed by using functional gene assignments, determined on the basis of bioinformatics analysis and further supported by in vivo gene inactivation experiments. Overall, this work provides new insights into the biosyntheses of the GV and VG streptogramins that are potentially applicable to a host of combinatorial biosynthetic scenarios.
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