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Under the guidance of genome mining combined with bioassay-coupled metabolomic analyses, an unprecedented macrodiolide sanyensin (1), with two flexible macrolides fused by the rigid oxabicyclo[3.3.1]nonane core, was isolated from the deep-sea-derived Streptomycessp. OUCT16-30. The stereochemistry of 1was established by NOEs (nuclear Overhauser effects), J-based configuration analysis, Marfey’s analysis, and together with a newly introduced stereochemical study workflow, which greatly shortens the time to obtain correct conformations of flexible structures based on the NMR constraints, thus leading to reliable quantum chemical calculations to establish the absolute configurations. This workflow is expected to have broad applicability for elucidating the stereochemistry of flexible natural products. The macrodiolide framework of 1is proposed to be formed through a biocatalytic cyclodimerization, followed by a series of nonenzymatic reactions. This work leads to new insights into the unexplored biosynthetic potential of deep-sea microbes and also provides a practical streamline for efficient mining of novel natural products, from discovery to stereochemical finalization.

The integration of NMR-metabolomic and genomic analyses can provide enhanced identification of structural properties as well as key biosynthetic information, thus achieving the targeted discovery of new natural products. For this purpose, NMR-based metabolomic profiling of the marine-derived Streptomycessp. S063 (CGMCC 14582) was performed, by which N-methylated peptides possessing unusual negative 1H NMR chemical shift values were tracked. Meanwhile, genome mining of this strain revealed the presence of an unknown NRPS gene cluster (len) with piperazic-acid-encoding genes (lenEand lenF). Under the guidance of the combined information, two cyclic decapeptides, lenziamides D1 (1) and B1 (2), were isolated from Streptomycessp. S063, which contains piperazic acids with negative 1H NMR values. The structures of 1and 2were determined by extensive spectroscopic analysis combined with Marfey’s method and ECD calculations. Furthermore, we provided a detailed model of lenziamide (1and 2) biosynthesis in Streptomycessp. S063. In the cytotoxicity evaluation, 1and 2showed moderate growth inhibition against the human cancer cells HEL, H1975, H1299, and drug-resistant A549–taxol with IC50values of 8–24 μM.

AbstractSeismic disaster risk assessment results are an important way to reduce disaster losses and casualties. In this article, a seismic disaster risk assessment method is constructed based on the lethal level, and a quantitative assessment of the earthquake disaster risk in Guangzhou is carried out. There are four typical building types in this study area: brick-wood structures, brick-concrete structures, reinforced concrete structures, and civil structures. Typical building structural components (vertical load-bearing component, ring beam, mortar of infilled wall, roof or floor structure, foundation, height of building, nonstructural component, anti-seismic joint or other anti-seismic measures) are selected to build the lethal level index system of buildings. On the basis of the field survey, a lethal level of 431 survey points is obtained. The average lethal level in urban areas is 0.3476, and in rural areas is 0.4198, the overall lethal level of each township is 0.389, and the errors between the urban and rural areas are 0.0414 and 0.0308, and the fitting results coefficient of determination (R2) values are 0.6803 and 0.6714, respectively, the results is good. Furthermore, considering the seismic hazard (peak ground acceleration, PGA), population exposure and lethal level, the seismic disaster risk distribution of the Guangzhou area is determined. Under different intensities, the risk of death has shown obvious characteristics, as the intensity increases, the number of possible deaths increases rapidly, ranging from a few to several thousand, the higher risk areas are relatively fixed, generally mainly located in the central city, the quantitative assessment results of disaster risk also have obvious directivity. The areas with the highest risk are located in most areas of Tianhe District, Liwan District and Haizhu District, the highest grid death result is more than 1; the lethal level of Baiyun District and Huangpu District is low, but the death risk is also higher, generally between 0.5 and 1, in rural areas in the southern and northern regions of Guangzhou, the risk is relatively low, generally between 0 and 0.5. The distribution map of seismic disaster risk can provide solid scientific and technological support for the government to investigate potential risk points.

Nine new (1–3, 5–8, 11, and 12; named filipins VI–XIV) and three known (4, 9, and 10) filipin-type polyene macrolides were isolated from the deep-sea-derived Streptomyces antibioticusOUCT16-23 using a genome-guided strategy coupled with bioassay. Their structures were elucidated based on the extensive MS and NMR spectroscopic analyses together with ECD calculations. In an antifungal assay, compounds 4, 5, and 7–10showed different degrees of growth inhibition against Candida albicanswith minimum inhibitory concentrations (MICs) of 1.56–12.5 μg/mL, by which the alkyl side-chain substitution affecting the activity was preliminarily studied. A biosynthetic pathway to 1–12in S. antibioticusOUCT16-23 is also proposed.

Macrolactins (MLNs) are a class of important antimacular degeneration and antitumor agents. Malonylated/succinylated MLNs are even more important due to their efficacy in overcoming multi-drug-resistant bacteria. However, which enzyme catalyzes this reaction remains enigmatic. Herein, we deciphered a β-lactamase homologue BmmI to be responsible for this step. BmmI could specifically attach C3–C5 alkyl acid thioesters onto 7-OH of MLN A and also exhibits substrate promiscuity toward acyl acceptors with different scaffolds. The crystal structure of BmmI covalently linked to the succinyl group and systematic mutagenesis highlighted the role of oxyanion holelike geometry in the recognition of carboxyl-terminated acyl donors. The engineering of this geometry expanded its substrate scope, with the R166A/G/Q variants recognizing up to C12 alkyl acid thioester. The structure of BmmI with acyl acceptor MLN A revealed the importance of Arg292 in the recognition of macrolide substrates. Moreover, the mechanism of the BmmI-catalyzed acyltransfer reaction was established, unmasking the deft role of Lys76 in governing acyl donors as well as catalysis. Our studies uncover the delicate mechanism underlying the substrate selectivity of acyltransferases, which would guide rational enzyme engineering for drug development.

Disruption of an aminotransferase family gene dtlAactivated the production of a novel dimeric benzoic polyene acids (BPAs), named youssoufene A1 (1), along with four new (2–5, youssoufenes B1–B4) and a known (6) monomeric BPA in the marine-derived Streptomyces youssoufiensisOUC6819. The structures of 1–5were elucidated by extensive spectroscopic and computational approaches. Youssoufene A1 (1) exhibited notably increased growth inhibition (MIC = 12.5 μg/mL) against multidrug resistant Enterococcus faecaliscompared to monomeric structures (2–6).

Exploration of unstable compounds is a rarely explored area of natural product research. We describe the integration of genomic and metabolomic analyses with bioassay-guided compound mining to effectively explore unstable bacillaenes. New bacillaene structures (2, 4, and 5) were identified from compound mixtures using the DANS-SVI (differential analysis of 2D NMR spectrum–single spectrum with variable intensities) method, which were further verified by the isolation of the pure compounds under strictly controlled conditions. Compound 1exhibited antibacterial activity against multi-drug-resistant bacterial strains, while glycosylation decreased the activity of the bacillaene scaffold.

A combined strategy of 2D-NMR-metabolomics-driven substructure tracking with genome mining led to the targeted discovery of 10 nocobactin-type lipopeptides (1–10) from the Arctic-derived phychrophillic Nocardiasp. L-016, among which 1–5are new compounds, named nocardimicins S–W. The phenoxazole moiety in 1–10, featuring unique NMR values and correlations, was used as a probe for tracking nocardimicin analogues. The structures of 1–5were established based on extensive MS and NMR spectroscopic analyses. The biosynthesis of nocardimicins (1–10) in Nocardiasp. L-016 is proposed to be achieved by the nocbiosynthetic gene cluster, which is composed of two sub-gene clusters (I and II) separated by a 228 kb region. Compounds 1–10showed moderate inhibition against human cancer cell lines of HCT116 and HepG2 with IC50values in the range of 3.5–10.2 μM. This work provides an effective application of paired-omics technologies in the discovery of new natural products.

Two new staurosporine derivatives, staurosporines M1 and M2 (4and 5), in addition to five previously reported metabolites (1–3, 6, and 7), were generated by the heterologous expression of engineered spcgene clusters in Streptomyces coelicolorM1146. The structures of these derivatives were determined by a combination of spectroscopic methods and CD measurement. Compounds 1, 2, 4, and 5showed effective activities against three tumor cell lines (HCT-116, K562, and Huh 7.5), and 3was active against HCT-116 and K562 cells. In addition, compounds 3and 5showed undetectable toxicity up to 100 μM toward the normal hepatic cell line LO2. Based on the IC50values, their structure and activity relationships are discussed.

A novel cystine knot peptide, asteropsin E (ASPE), was isolated from an Asteropussp. marine sponge. The primary, secondary, and tertiary structures of ASPE were determined by high-resolution 2D NMR spectroscopy (900 MHz). With the exception of an N-terminal modification, ASPE shares properties with the previously reported asteropsins A–D, that is, the absence of basic residues, a highly acidic nature, conserved structurally important residues (including two cis-prolines), and a highly conserved tertiary structural framework. ASPE was found to be remarkably stable to gastrointestinal tract enzymes (chymotrypsin, elastase, pepsin, and trypsin) and to human plasma.

Four new amino acid derivatives, herdmanines A–D (1–4), were isolated from the marine ascidian Herdmania momus. Herdmanines A–C contain the unusual d-form of arginine. Compounds 3and 4had a moderate suppressive effect on the production of NO, with IC50values of 96 and 9 μM, respectively. These compounds were found to inhibit the mRNA expression of iNOS. The inhibitory activities on the production and mRNA expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 were evaluated.

Two new (1and 2) along with six known (3–8) dixiamycins were isolated from the culture broth of a cold-seep-derived actinomycete, Streptomyces olivaceusOUCLQ19-3. Structures of the isolated compounds were elucidated based on extensive MS and NMR spectroscopic analyses together with ECD calculations. In the antibacterial test, compounds 1–8exhibited notable growth inhibitions against a panel of multi-drug-resistant (MDR) strains with MIC values of 0.78–6.25 μg/mL, among which 1, 2, and 5–7were more potent than the positive control tetracycline.

A terahertz (THz) broadband polarizer using bilayer subwavelength metal wire-grid structure on both sides of polyimide film is simulated by the finite-difference time-domain method. We analyze the effect of film ­thickness, material loss, and lateral shift between two metallic gratings on the performance of the THz ­polarizer. Bilayer wire-grid polarizers are fabricated by a simple way of laser induced and non-electrolytic plating with copper. The THz time-domain spectroscopy measurements show that in 0.2-1.6 THz frequency range, the extinction ratio is better than 45 dB, the average extinction ratio reaches 53 dB, and the ­transmittance exceeds 67%, which shows great advantage over conventional single wire-grid THz polarizer.