Targeted high-level production of chuangxinmycin and its halogenated derivatives with antitubercular activity.

Background: Chuangxinmycin (CM) is an old antibiotic from Actinoplanes tsinanensis CPCC, 200056, characterized by a dihydrothiopyrano[4,3,2-cd]indole scaffold and potent activity against Mycobacterium tuberculosis. Its congener norchuangxinmycin (NCM), which lacks antibacterial activity against various bacteria, unexpectedly retains antitubercular activity, indicating new mechanisms of action against M. tuberculosis in addition to tryptophan-tRNA synthetase inhibition.

Selective Inhibition Mechanism of Tryptophan-tRNA Synthetase by Chuangxinmycin.

Tuberculosis (TB), caused by (Mtb), represents a global health challenge, necessitating new treatments with distinct mechanisms of action (MOA) to combat drug resistance. Chuangxinmycin (CM), characterized by its indole-dihydrothiopyran heterocyclic skeleton, exhibits potent antibacterial activity both and , with a minimum inhibitory concentration (MIC) of 0.25 μg/mL against Mtb.

Iterative Methylation Leads to 3-Methylchuangxinmycin Production in CPCC 200056.

A new congener of chuangxinmycin (CM) was identified from CPCC 200056. Its structure was determined as 3-methylchuangxinmycin (MCM) by 1D and 2D NMR. MCM could be generated from CM by heterologous expression of the vitamin B-dependent radical SAM enzyme CxnA/A responsible for methylation of 3-demethylchuangxinmycin (DCM) in CM biosynthesis, indicating that CxnA/A could perform iterative methylation for MCM production.

Geninthiocins E and F, two new cyclic thiopeptides with antiviral activities from soil-derived Streptomyces sp. CPCC 200267 using OSMAC strategy.

On the basis of the one strain-many compounds (OSMAC) strategy, two new cyclic thiopeptides, geninthiocins E and F, together with four known geninthiocin derivatives, geninthiocins A, B, C, and val-geninthiocin were isolated from Streptomyces sp. CPCC 200267. Their structures and absolute configurations were elucidated by extensive spectroscopic analyses and Marfey's method.

Isatropolone/isarubrolone C from Streptomyces with biological activity of inducing incomplete autophagy.

Isatropolones/isarubrolones are Streptomyces secondary metabolites featuring a tropolone ring in the pentacyclic scaffolds of these molecules. They are able to induce complete autophagy in human HepG2 cells. Here, methyl isatropolones (1-2) and isarubrolone (3) are identified from Streptomyces CPCC 204095.

Production of chain-extended cinnamoyl compounds by overexpressing two adjacent cluster-situated LuxR regulators in C-1027.

Natural products from microorganisms are important sources for drug discovery. With the development of high-throughput sequencing technology and bioinformatics, a large amount of uncharacterized biosynthetic gene clusters (BGCs) in microorganisms have been found, which show the potential for novel natural product production. Nine BGCs containing PKS and/or NRPS in C-1027 were transcriptionally low/silent under the experimental fermentation conditions, and the products of these clusters are unknown.

Dihydroisatropolone C from and Its Implication in Tropolone-Ring Construction for Isatropolone Biosynthesis.

Isatropolones/isarubrolones are actinomycete secondary metabolites featuring a tropolone-ring in their structures. From the isatropolone/isarubrolone producer sp. CPCC 204095, 7,12-dihydroisatropolone C (HITC) is discovered and identified as a mixture of two interchangeable diastereomers differing in the C-6 configuration.

Mintaimycins, a Group of Novel Peptide Metabolites from sp. C-3509.

A group of peptide metabolites (-), designated as mintaimycins, were isolated from sp. C-3509. The planar structures of mintaimycins were determined by combination of mass spectrometry, 1D and 2D NMR spectroscopy, and the stereochemistry of mintaimycins were partially resolved by Marfey's or Mosher's method.

Isarubrolone C Promotes Autophagic Degradation of Virus Proteins via Activating ATG10S in HepG2 Cells.

Isarubrolone C is a bioactive polycyclic tropoloalkaloid from . Our previous study showed that isarubrolone C could trigger autophagy. Here, we report isarubrolone C potential in broad-spectrum antiviral effect and its antiviral mechanism .

Cytochrome P450 Monooxygenase for Catalyzing C-42 Hydroxylation of the Glycine-Derived Fragment in Hangtaimycin Biosynthesis.

A hybrid -AT PKS/NRPS gene cluster was identified with defined boundaries for hangtaimycin biosynthesis in CPCC200148. Deoxyhangtaimycin, a new derivative of hangtaimycin, was identified from the gene knockout mutant. In vitro biochemical assays demonstrated that the cytochrome P450 monooxygenase Htm11 was responsible for the stereoselective hydroxylation of deoxyhangtaimycin to hangtaimycin.

The Cytochrome P450 Catalyzing C-S Bond Formation in S-Heterocyclization of Chuangxinmycin Biosynthesis.

Microbial sulfur-containing secondary metabolites show various biological activities, but the C-S bond-forming in their biosynthetic metabolism has not been thoroughly understood. Here, we present genetic, biochemical and structural characterization of a cytochrome P450 monooxygenase CxnD exhibiting C-S bond forming activity in S-heterocyclization of chuangxinmycin biosynthesis. In vivo and in vitro analyses demonstrated that CxnD generated an indole-fused dihydrothiopyran skeleton from a L-Trp-derived thiol intermediate.

Cervinomycins C with cytotoxic and antibacterial activity from Streptomyces sp. CPCC 204980.

Polycyclic xanthones are secondary metabolites from actinomycetes and cervinomycin A and B are bioactive 26-membered polycyclic xanthones from Streptomyces sp. CPCC 204980. Herein, we report cervinomycins C (1-4) from the same strain.

1-hydroxy-7-oxolavanducyanin and Δ-6″-hydroxynaphthomevalin from Streptomyces sp. CPCC 203577.

Lavanducyanin is a bioactive phenazine-containing secondary metabolite, and naphthomevalin is an antibacterial polyketide secondary metabolite. Herein, new analogues of lavanducyanin (2) and of naphthomevalin (4), together with lavanducyanin (1) and naphthomevalin (3), were identified from Streptomyces sp. CPCC 203577, an actinomycete soil isolate.

Cytotoxic and Antibacterial Cervinomycins B from a Species.

AntiSMASH analysis of genome DNA of CPCC 204980, a soil isolate with potent antibacterial activity, revealed a gene cluster for polycyclic xanthones. A subsequent chemical study confirmed that the microorganism produced polycyclic xanthone cervinomycin A () and the new congeners cervinomycins B (-). The structures of - were determined by comprehensive analyses of MS and NMR data, which indicated that - featured a common dihydro-D ring in the polycyclic xanthone core moiety of their molecules.

Genome-Guided Discovery of Pretilactam from ATCC 31565.

is a small but well-known genus of actinomycetes for production of ansamitocin, the payload component of antibody-drug conjugates against cancers. However, the secondary metabolite production profile of ATCC 31565, the most famous producer of ansamitocin, has never been fully explored. Our antiSMASH analysis of the genomic DNA of ATCC 31565 revealed a NRPS-PKS gene cluster for polyene macrolactam.

Isarubrolones Containing a Pyridooxazinium Unit from Streptomyces as Autophagy Activators.

Isarubrolones are bioactive polycyclic tropoloalkaloids from Streptomyces. Three new isarubrolones (2-4), together with the known isarubrolone C (1) and isatropolones A (5) and C (6, 3( R)-hydroxyisatropolone A), were identified from Streptomyces sp. CPCC 204095.

Geninthiocins C and D from Streptomyces as 35-membered macrocyclic thiopeptides with modified tail moiety.

Geninthiocin is a thiopeptide with 35-membered macrocyclic core moiety. It has potent anti-Gram-positive (G) bacteria activity. Herein, we reported two new congeners (2-3) of geninthiocin (geninthiocin A, 1) from Streptomyces sp.

Quinohemanine, a quinoxalinone-bohemamine hybrid compound from Streptomyces sp. CPCC 200497.

A quinoxalinone-bohemamine hybrid compound quinohemanine (1), together with 1-methyl-2(H)-quinoxalin-2-one (2), was isolated from Streptomyces sp. CPCC 200497, a producer of quinomycins and bohemamines. Compounds 1 and 2 were purified using standard chromatographic methods, and their structures were defined through interpretation of HRMS, 1D, and 2D NMR data.

Biosynthesis of antibiotic chuangxinmycin from .

Chuangxinmycin is an antibiotic isolated from CPCC 200056 in the 1970s with a novel indole-dihydrothiopyran heterocyclic skeleton. Chuangxinmycin showed antibacterial activity and efficacy in mouse infection models as well as preliminary clinical trials. But the biosynthetic pathway of chuangxinmycin has been obscure since its discovery.

Cytotoxic Dibohemamines D-F from a Streptomyces Species.

Three dimeric analogues of bohemamines, dibohemamines D-F (1-3), together with dibohemamine A (4), were isolated from Streptomyces sp. CPCC 200497. Their structures were solved using a combination of mass spectrometry, 1D and 2D NMR spectroscopy, and CD.

Three structurally-related impurities in norvancomycin drug substance.

Norvancomycin (NVCM) is widely used in China to treat bacterial infections of Gram-positive cocci and bacilli, especially infections of methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis. This study is a chemical investigation of the drug substance of NVCM, and led to the identification, by 1D, 2D NMR spectra and HRESIMS, of three as yet undescribed impurities, one D-O-E ring expanded NVCM analog (1) and two derivatives of NVCM lacking sugars (2, 3).