Bingya Jiang

Six new kromycin-type macrolides, kromycins B–G (1–6), and with the known kromycin A (7), were isolated from Streptomyces narbonensis sp. CPCC 206470 guided by the Global Natural Products Social Molecular Networking (GNPS) analysis. Their structures were comprehensively established by extensive spectroscopic analyses, time-dependent density functional theory electronic circular dichroism (TDDFT-ECD) comparison, and single-crystal X-ray diffraction analysis. These compounds represent a structurally distinct subclass of 14-membered macrolides. Compound 7 exhibited substantial neuroprotective activity by inhibiting Aβ42 aggregation and ameliorating oxidative stress and neuroinflammation in N2a neuronal cells. It enhanced antioxidant enzyme activities (SOD and CAT) and suppressed nitric oxide production. Genomic analysis identified a pikromycin-related biosynthetic gene cluster in the producing strain. This study expands the chemical diversity of kromycin-type natural products and highlights their potential as multitarget therapeutic agents for neurodegenerative diseases.

Glycosyltransferase AcbI from Pantoea agglomerans ZJU23 was first expressed and biochemically elucidated to catalyze the last-step glycosylation of herbicolin A (1) with antifungal activity. By AlphaFold2 prediction, molecular docking, and site-directed mutagenesis experiments, AcbI was hypothesized to function via a working model resembling the catalytic mechanism of type A glycosyltransferase, with the exception that the R75 residue in AcbI can electrostatically stabilize the leaving phosphate of UDP-d-Glc. Our findings provide novel highlights and tools for the glycosylation of cyclolipopeptides.

Isatropolone C from Streptomyces sp. CPCC 204095 features a fused cyclopentadienone-tropolone-oxacyclohexadiene tricyclic moiety in its structure. Herein, we report an isatropolone C dimer derivative, di-isatropolone C, formed spontaneously from isatropolone C in methanol. Notably, the structure of di-isatropolone C resolved by NMR reveals a newly formed cyclopentane ring to associate the two isatropolone C monomers. The configurations of four chiral carbons, including a ketal one, in the cyclopentane ring are assigned using quantum NMR calculations and DP4+ probability. The plausible molecular mechanism for di-isatropolone C formation is proposed, in which complex dehydrogenative C-C bond coupling may have happened to connect the two isatropolone C monomers. Like isatropolone C, di-isatropolone C shows the biological activity of inducing autophagy in HepG2 cells.

A new congener of chuangxinmycin (CM) was identified from Actinoplanes tsinanensis CPCC 200056. Its structure was determined as 3-methylchuangxinmycin (MCM) by 1D and 2D NMR. MCM could be generated in vivo from CM by heterologous expression of the vitamin B₁₂-dependent radical SAM enzyme CxnA/A₁ responsible for methylation of 3-demethylchuangxinmycin (DCM) in CM biosynthesis, indicating that CxnA/A₁ could perform iterative methylation for MCM production. In vitro assays revealed significant activities of CM, DCM, and MCM against Mycobacterium tuberculosis H37Rv and clinically isolated isoniazid/rifampin-resistant M. tuberculosis, suggesting that CM and its derivatives may have potential for antituberculosis drug development.

Isatropolones/isarubrolones are actinomycete secondary metabolites featuring a tropolone-ring in their structures. From the isatropolone/isarubrolone producer Streptomyces sp. CPCC 204095, 7,12-dihydroisatropolone C (H₂ITC) is discovered and identified as a mixture of two interchangeable diastereomers differing in the C-6 configuration. As a major metabolite in the mycelial growth period of Streptomyces sp. CPCC 204095, H₂ITC can be oxidized spontaneously to isatropolone C (ITC), suggesting H₂ITC is the physiological precursor of ITC. Characterization of H₂ITC makes us propose dihydrotropolone-ring construction in the biosynthesis of isatropolones.

A hybrid trans-AT PKS/NRPS gene cluster htm was identified with defined boundaries for hangtaimycin biosynthesis in Streptomyces spectabilis CPCC200148. Deoxyhangtaimycin, a new derivative of hangtaimycin, was identified from the htm11 gene knockout mutant. In vitro biochemical assays demonstrated that the cytochrome P450 monooxygenase Htm11 was responsible for the stereoselective hydroxylation of deoxyhangtaimycin to hangtaimycin. More importantly, deoxyhangtaimycin showed activity against influenza A virus at the micromolar level, highlighting its potential as an antiviral lead compound.

A group of peptide metabolites (1–4), designated as mintaimycins, were isolated from Micromonospora 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. Mintaimycins featured a central β-methylphenylalanine or phenylalanine linked at its amino group with 5-methyl-2-hexenoic acid, and at its carboxyl group with 5-hydroxy-norleucine or leucine that combined a derivative of hexanoic acid or 4-methylpentanoic acid. Mintaimycin A₁ (1), the principal component, was found to exhibit the biological activity of inducing pre-adipocyte differentiation of 3T3-L1 fibroblast cells at 10.0 μmol/L.

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 (1–4) from the same strain. The structures of 1–4 were determined by 1D- and 2D-NMR, or single-crystal X-ray diffraction. Compounds 1–4 feature the open or loss of A (oxazolidine) ring in their angular polycyclic framework compared with cervinomycin B. Compounds 1–4 showed potent cytotoxicity against human cancer cell lines HCT116 and BxPC-3, with IC₅₀ at 0.9–801.0 nM and strong anti-Gram-positive bacterial activity.

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. The structures of 2 and 4 were elucidated as 1-hydroxy-7-oxolavanducyanin and Δ^7″,8″-6″-hydroxynaphthomevalin, respectively, by 1D and 2D NMR. Antibacterial assays revealed that 2 had significant but reduced anti-Gram-positive bacterial activity compared with 1, and 4 was devoid of anti-Gram-positive bacterial activity. This indicated that the phenazinone nucleus in lavanducyanin and the monoterpene side chain in naphthomevalin might be important for their anti-Gram-positive bacterial activity. Compounds 1–4 were all inactive against Gram-negative bacteria.

AntiSMASH analysis of genome DNA of Streptomyces 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 A₂ (1) and the new congeners cervinomycins B_1–4 (2–5). The structures of 1–5 were determined by comprehensive analyses of MS and NMR data, which indicated that 2–5 featured a common dihydro-D ring in the polycyclic xanthone core moiety of their molecules. 2–5 are toxic to human cancer cells and active against Gram-positive bacteria.