Antimicrobial spiroketal macrolides and dichloro-diketopiperazine from Micromonospora sp. FIMYZ51.

Four compounds (1-4) featuring with an L-rhodinose and spiroketal, possess uncommon continuous hydroxy groups in the macrolide skeleton, and a dichloro-diketopiperazine (5) were isolated from a marine derived Micromonospora sp. FIMYZ51. The determination of the relative and absolute configurations of all isolates was achieved by extensive spectroscopic analyses, single-crystal X-ray diffraction analysis, and ECD calculations. According to structural characteristic and genomic sequences, a plausible biosynthetic pathway for compound 1-4 was proposed and a spirocyclase was inferred to be responsible for the formation of the rare spirocyclic moiety. Compounds 1-4 exhibited potent antifungal activities which is equal to itraconazole against Aspergillus niger. Compounds 1-5 exhibited different degree of inhibitory activities against opportunistic pathogenic bacteria of endocarditis (Micrococcus luteus) with MIC values ranging from 0.0625 µg/mL to 32 µg/mL. Compounds 2 and 3 showed moderate cytotoxicity against drug-resistant tumor cell lines (Namalwa and U266). The result not only provides active lead-compounds, but also reveal the potential of the spirocyclase gene resources from Micromonospora sp., which highlights the promising potential of the strain for biomedical applications.

Advancing Natural Product Discovery: A Structure-Oriented Fractions Screening Platform for Compound Annotation and Isolation.

Natural product discovery is hindered by the lack of tools that integrate untargeted nuclear magnetic resonance and mass spectrometry data on a library scale. This article describes the first application of the innovative NMR/MS-based machine learning tool, the "Structure-Oriented Fractions Screening Platform (SFSP)", enabling functional-group-guided fractionation and accelerating the discovery and characterization of undescribed natural products. The concept was applied to the extract of a marine fungus known to be a prolific producer of diverse natural products. With the assistance of SFSP, we isolated 24 flavipidin derivatives and five phenalenone analogues from Aspergillus sp. GE2-6, revealing 27 undescribed compounds. Compounds 7-22 were proposed as isomeric derivatives featuring a 5/6-ring fusion, formed by the dimerization of flavipidin E (5). Compounds 23 and 24 were envisaged as isomeric derivatives with a 6/5/6-ring fusion, generated through the degradation of two flavipidin E molecules. Furthermore, flavipidin A (1) and asperphenalenone E (28) exhibited potent anti-influenza (PR8) activities, with IC50 values of 21.9 ± 0.2 and 12.9 ± 0.1 µM, respectively. Meanwhile, asperphenalenone (26) and asperphenalenone P (27) treatments exhibited significant inhibition of HIV pseudovirus infection in 293FT cells, boasting IC50 values of 6.1 ± 0.9 and 4.6 ± 1.1 µM, respectively. Overall, SFSP streamlines natural product isolation through NMR and MS data integration, as showcased by the discovery of numerous undescribed flavipidins and phenalenones based on NMR olefinic signals and low-field hydroxy signals.

Kueishanamides A and B from the Hydrothermal Vent Sediment Derived Streptomyces sp. WU20.

Marine actinomycetes are known for their production of remarkable organic molecules, particularly those featuring polyoxygenated long-chain backbones. Determining the absolute configurations of these compounds remains a challenging task even today. In this study, we successfully established the planar structures and absolute configurations of two highly flexible amide alkaloids from Streptomyces sp. WU20: kueishanamides A (1) and B (2). These compounds possess a C13 linear backbone and each contains five stereogenic carbon centers. Our approach involved a combination of spectroscopic and computational methods, including J-based configurational analysis and VCD calculations, ensuring the unambiguous determination of their configurations. Kueishanamide A (1) and kueishanamide B (2) showed moderate antifungal activity against pathogenic fungus Crytococcus neoformans, with MIC values of 25 µg/mL each.

Specialized metabolites of the fungal genus Phomopsis: Structures, bioactivities and biosynthesis.

Fungi are important resources of novel bioactive compounds which have a high potential to be drug leads or candidates for further pharmacological applications. Phomopsis, a genus widely distributed in the environment, can produce various types of compounds including polyketides, alkaloids, terpenoids, cytochalasins, steroids and flavonoids. The metabolites of Phomopsis sp. showed diverse bioactivities such as antibacterial, anti-inflammatory, antimalarial, and so on, many of which may influence the physiological behaviour of the host plants. In this review, we focus on the chemical structures and biological activities of 183 specialized metabolites isolated from Phomopsis sp. in the decade (2013-2022). Moreover, the biosynthetic pathways of some typical components are summarized.

Antifungal polyketides from the marine-derived fungus Nigrospora sp. MG36-1.

Three new polyketides, a griseofulvin derivative 1, a hydroanthraquinone derivative 8 and a pyranolactone derivative 10, together with eight known compounds (2-7, 9 and 11), were isolated from the marine-derived fungus Nigrospora sp. MG36-1. The structures of the three new compounds were unambiguously determined by nuclear magnetic resonance (NMR), mass spectrometry, 13C NMR calculation in combination with DP4+ and ECD calculations. The antitumor, antibacterial and antifungal activities of the compounds 1-9 were evaluated in vitro. Compound 1 showed antibacterial activity against Acinetobacter baumannii with MIC 42.5 µg/mL. Compounds 1 and 8 exhibited antifungal activity against Candida albicans with MICs 21.5 µg/mL and 17.5 µg/mL, respectively.

Talaropeptins A and B, Tripeptides with an N-trans-Cinnamoyl Moiety from the Marine-Derived Fungus Talaromyces purpureogenus CX11.

We report the discovery of talaropeptins A (1) and B (2), tripeptides with an unusual 5/6/5 heterocyclic scaffold and an N-trans-cinnamoyl moiety, which were identified from the marine-derived fungus Talaromyces purpureogenus CX11. A bioinformatic analysis of the genome of T. purpureogenus CX11 and gene inactivation revealed that the biosynthesis of talaropeptins involves a nonribosomal peptide synthase gene cluster. Their chemical structures were elucidated using a combination of 1D and 2D NMR spectroscopy and mass spectrometry. The absolute configurations of 1 and 2 were established by electronic circular dichroism calculations and Marfey's method. The plausible biosynthesis of 1 and 2 is also proposed on the basis of gene deletion, substrate feeding, and heterologous expression. Compounds 1 and 2 showed moderate antifungal activity against phytopathogenic fungus Fusarium oxysporum with MIC values of 12.5 and 25 µg/mL, respectively.

Hijacking a Linaridin Biosynthetic Intermediate for Lanthipeptide Production.

Linaridins and lanthipeptides are two classes of natural products belonging to the ribosomally synthesized and posttranslationally modified peptide (RiPP) superfamily. Although these two RiPP classes share similar structural motifs such as dehydroamino acids and thioether-based cross-links, the biosynthesis of linaridins and lanthipeptides involved distinct sets of enzymes. Here, we report the identification of a novel lanthipeptide cypepeptin from a recombinant strain of Streptomyces lividans, which harbors most of the cypemycin (a prototypic linaridin) biosynthetic gene cluster but lacks the decarboxylase gene cypD. In contrast to the generally believed structure of cypemycin, multiple d-amino acids and Z-dehydrobutyrines were observed in both cypepeptin and cypemycin, and the stereochemistry of each amino acid was established by the extensive structural analysis in combination with genetic knockout and mutagenesis studies. Comparative analysis of cypemycin and cypepeptin showed that the aminovinyl-cysteine (AviCys) moiety of cypemycin plays an essential role in disrupting the cell integrity of M. luteus, which cannot be functionally substituted by the structurally similar lanthionine moiety.

Heterologous expression and characterization of glycoside hydrolase with its potential applications in hyperthermic environment.

With the progressive focus on renewable energy via biofuels production from lignocellulosic biomass, cellulases are the key enzymes that play a fundamental role in this regard. This study aims to unravel the characteristics of Thermotoga maritima MSB8 (Tma) (a hyperthermophile from hot springs) thermostable glycoside hydrolase enzyme. Here, a glycoside hydrolase gene of Thermotoga maritima (Tma) was heterologously expressed and characterized. The gene was placed in the pQE-30 expression vector under the T5 promotor, and the construct pQE-30-Gh was then successfully integrated into Escherichia coli BL21 (DH5α) genome by transformation. Sequence of the glycoside hydrolase contained an open reading frame of 2.124 kbp, encoded a polypeptide of 721 amino acid residues. The molecular weight of the recombinant protein estimated was 79 kDa. The glycoside hydrolase was purified by Ni+2-NTA affinity chromatography and its enzymatic activity was investigated. The recombinant enzyme is highly stable within an extreme pH range (2.0-7.0) and highly thermostable at 80 °C for 72 h indicating its viability in hyperthermic environment and acidic nature. Moreover, the Ca2+ and Mn2+ introduction stimulated the residual activity of recombinant enzyme. Conclusively, the thermostable glycoside hydrolase possesses potential to be exploited for industrial applications at hyperthermic environment.

C-P Natural Products as Next-Generation Herbicides: Chemistry and Biology of Glufosinate.

In modern agriculture and weed management practices, herbicides have been widely used to control weeds effectively and represent more than 50% of commercial pesticides applied in the world. Herbicides with unique mechanisms of actions (MOA) have historically been discovered and commercialized every two or three years from the 1950s to the 1980s. However, this trend lowered dramatically as no herbicide with a novel MOA has been marketed for more than 30 years. The fast-growing resistance to commercial herbicides has reignited the agricultural chemical industry interest in new structural scaffolds targeting novel sites in plants. Carbon-phosphorus bonds (C-P) containing natural products (NPs) have played an essential role in herbicide discovery as the chemical diversity, and the promising bioactivity of natural C-P phytotoxins can provide exciting opportunities for the discovery of both natural and semisynthetic herbicides with novel targets. Among commercial herbicides, glyphosate (Roundup), a famous C-P containing herbicide, is by far the most universally used herbicide worldwide. Furthermore, glufosinate is one of the most widely used natural herbicides in the world. Therefore, C-P NPs are a treasure for discovering new herbicides with novel mechanisms of actions (MOAs). Here, we present an overview of the chemistry and biology of glufosinate including isolation and characterization, mode of action, herbicidal use, biosynthesis, and chemical synthesis since its discovery in order to not only help scientists reassess the role of this famous herbicide in the field of agrichemical chemistry but also build a new stage for discovering novel C-P herbicides with new MOAs.

Discovery of Three New Phytotoxins from the Fungus Aspergillus nidulans by Pathway Inactivation.

Fungi are a source of novel phytotoxic compounds to be explored in the search for effective and environmentally safe herbicides. The genetic inactivation of the biosynthetic pathway of the new phytotoxin cichorine has led to the isolation of three novel phytotoxins from the fungus Aspergillus nidulans: 8-methoxycichorine (4), 8-epi-methoxycichorine (5), and N-(4'-carboxybutyl) cichorine (6). The structure of the new compounds was clearly determined by a combination of nuclear magnetic resonance (NMR) analysis and high-resolution electrospray ionization (HRESIMS). The phytotoxic bioassay was studied on leaves from Zea mays and Medicago polymorpha L. at the concentration of 5 × 10-3 M by using a moist chamber technique. Novel phytotoxins 8-methoxycichorine (4), 8-epi-methoxycichorine (5), and N-(4'-carboxybutyl) cichorine (6) exhibited a better phytotoxic effect than cichorine.