Antibacterial and cytotoxic angucyclines discovered by heterologous expression of a type II polyketide gene cluster.

Three new aromatic polyketides, spirocyclione C (1) and angumycinones E and F (2 and3), were isolated from the heterologous expression of a type II gene cluster in the strain of A3(2) assisted by the one strain many compounds (OSMAC) strategy. The structures and absolute configurations of these compounds were elucidated by extensive NMR, MS, theoretical NMR calculations, DP4+ probability analysis, and ECD analyses. Notably, compound 1 represents the first example of an angucycline structure with an unusual oxaspiro[5.

The thiodiketopiperazine derivatives shovelmycin A-B and ansamycin derivative divergolide X from the cold-seep-derived Streptomyces olivaceus HDN22-001.

Three new compounds including two thiodiketopiperazine derivatives shovelmycins A-B (1-2), and one ansamycin derivative divergolide X (3) were isolated and identified from the culture extract of Streptomyces olivaceus HDN22-001, a marine actinomycete obtained from the deep-sea cold seep sediment sample collected from the South China Sea. Their structures and absolute configurations were determined by spectroscopic analyses and ECD calculations. Compound 1 exhibited the strongest DPPH radical scavenging activity with an IC value of 10.

(±)-Feionemycin A and Chromonemycins A-D, Rearranged Aromatic Polyketides Uncovered by Type II Polyketide Gene Cluster Expression.

Two novel spiro aromatic polyketides, (+)- and (-)-feionemycin A (), along with four atypical angucyclinones named as chromonemycins A-D (-), were discovered through heterologous expression of a type II polyketide gene cluster, within which one previously characterized flavoprotein monooxygenase was deactivated. Among those structures, compound features an unprecedented oxaspiro[5.4]undecane architecture, and compounds - represent novel atypical angucyclinone variants derived from unusual cyclization of the polyketide chains.

Overexpression of a pathway-specific transcriptional factor CicD leads to the discovery of new phytotoxins in .

A NRPKS gene cluster in was activated by overexpression of the pathway-specific transcriptional factor CicD. Large-scale fermentation and chemical investigation of the engineered strain A1145/cicD led to the discovery of two new isoindolone-amino acid adducts, isoleucylcichorine (1) and leucylcichorine (2), along with three known derivatives. The structures of the new compounds were clearly determined by nuclear magnetic resonance (NMR) analysis, high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations.

Biosynthesis of Dothideomins Reveals a Fungal P450 That Constructs the Tricyclo[5.2.2.0.]undecane-Imbedded Core Skeleton.

Dothideomins are antibacterial bis(anthraquinone) polyketides isolated from the endophytic fungus sp. BMC-101, featuring a unique 6/6/6/5/6/6/6 heptacyclic scaffold imbedded with a tricyclo[5.2.

Discovery and Characterization of a Fungal N-acetylglucosamine Transferase in the Biosynthesis of Furanone Glycosides.

Malfilamentosides are a class of fungal secondary metabolites characterized by glycosylated furanone scaffold; however, the enzyme that catalyzes the -glycosylation of the furanone core with -acetylglucosamine (GlcNAc) has not yet been identified. In this study, we discovered and identified the biosynthetic gene cluster of the malfilamentosides. and investigations revealed that a glycosyltransferase, MftB, catalyzes the -glycosylation of the furanone scaffold with GlcNAc.

Characterization and structural analysis of a versatile aromatic prenyltransferase for imidazole-containing diketopiperazines.

Prenylation modifications of natural products play essential roles in chemical diversity and bioactivities, but imidazole modification prenyltransferases are not well investigated. Here, we discover a dimethylallyl tryptophan synthase family prenyltransferase, AuraA, that catalyzes the rare dimethylallylation on the imidazole moiety in the biosynthesis of aurantiamine. Biochemical assays validate that AuraA could accept both cyclo-(L-Val-L-His) and cyclo-(L-Val-DH-His) as substrates, while the prenylation modes are completely different, yielding C2-regular and C5-reverse products, respectively.

Naphpyrones A-H, Antibacterial Aromatic Polyketides Isolated from the A3(2)/ ΔH3.

, a common foodborne pathogen, has a close association with agriculture and food. With the rapid emergence and widespread dissemination of antimicrobial resistance, efforts have been directed toward developing and studying new antimicrobial compounds to inhibit the growth of and other foodborne pathogens, thereby preventing contamination and ensuring food safety. Herein, we reported eight new aromatic polyketides, naphpyrones A-H (-), from the heterologous expression strain A3(2)/ ΔH3.

Heterologous Expression of Type II PKS Gene Cluster Leads to Diversified Angucyclines in J1074.

Heterologous expression has emerged as an effective strategy in activating cryptic gene clusters or improving yield. Eight compounds were successfully obtained by heterologous expression of the type II PKS gene cluster derived from marine sp. HDN155000 in the chassis host J1074.

Novel antifungal talaroenamine L with unusual leptosphaeronyl moiety from marine-derived sp. HDN17-428 via HDACi elicitation.

Vorinostat elicitation of the deep-sea fungus sp. HDN17-428 resulted in the isolation of one new compound, talaroenamine L () with unusual leptosphaeronyl moiety and three known compounds (-). Structures of - were confirmed by extensive NMR, HRESIMS and OR calculations.

Polyketide Derivatives from the Mangrove-Derived Fungus sp. HDN15-312.

Four new polyketides, namely furantides A-B (-), talamin E () and arugosinacid A (), and two known polyketides were obtained from the mangrove-derived fungus sp. HDN15-312 using the One Strain Many Compounds (OSMAC) strategy. Their chemical structures, including configurations, were elucidated by detailed analysis of extensive NMR spectra, HRESIMS and ECD.

Biosynthesis of Atypical Angucyclines Unveils New Ring Rearrangement Reactions Catalyzed by Flavoprotein Monooxygenases.

Six new angucycline structures, including spirocyclione A (), which contains an unusual oxaspiro[5.5]undecane architecture, and its ring-A-cleaved product spirocyclione B (), were discovered by heterologous expression of a type II polyketide biosynthetic gene cluster captured from a marine actinomycete strain sp. HDN155000.

Sorbremnoids A and B: NLRP3 Inflammasome Inhibitors Discovered from Spatially Restricted Crosstalk of Biosynthetic Pathways.

Crosstalk-oriented chemical evolution of natural products (NPs) is an efficacious strategy for generating novel skeletons through coupling reactions between NP fragments. In this study, two NOD-like receptor protein 3 (NLRP3) inflammasome inhibitors, sorbremnoids A and B ( and ), with unprecedented chemical architectures were identified from a fungus . Compounds and exemplify rare instances of hybrid NPs formed via a major facilitator superfamily (MFS)-like enzyme by coupling reactive intermediates from two separate biosynthetic gene clusters (BGCs), and .

Discovery, Total Synthesis, and Anti-Inflammatory Evaluation of Naturally Occurring Naphthopyrone-Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors.

Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug.

Bacteriophage-resistant carbapenem-resistant Klebsiella pneumoniae shows reduced antibiotic resistance and virulence.

Phage therapy has shown great promise in the treatment of bacterial infections. However, the effectiveness of phage therapy is compromised by the inevitable emergence of phage-resistant strains. In this study, a phage-resistant carbapenem-resistant Klebsiella pneumoniae strain SWKP1711R, derived from parental carbapenem-resistant K.

Exploring the Diverse Landscape of Fungal Cytochrome P450-Catalyzed Regio- and Stereoselective Dimerization of Diketopiperazines.

Dimeric indole-containing diketopiperazines (di-DKPs) are a diverse group of natural products produced through cytochrome P450-catalyzed C-C or C-N coupling reactions. The regio- and stereoselectivity of these reactions plays a significant role in the structural diversity of di-DKPs. Despite their pivotal role, the mechanisms governing the selectivity in fungi are not fully understood.

Phenylhydrazone Alkaloids from the Deep-Sea Cold Seep Derived Fungus HDN21-0307.

Alkaloids with a phenylhydrazone architecture are rarely found in nature. Four unusual phenylhydrazone alkaloids named talarohydrazones A-D (-) were isolated from the deep-sea cold seep derived fungus HDN21-0307 using the one strain-many compounds (OSMAC) approach and MS/MS-based molecular networking (MN) combined with network annotation propagation (NAP) and the unsupervised substructure annotation method MS2LDA. Their structures were elucidated by spectroscopic data analysis, single-crystal X-ray diffraction, and quantum chemical calculations.

Antiviral and cytotoxic indole diterpenoids from the antarctic sponge-derived fungus HDN15-152.

One new indole diterpenoid, ascandinine T (), and three known analogues (-) were isolated from an Antarctic sponge-derived fungus HDN15-152. The structures, including absolute configurations, were established based on NMR, HRESIMS, and electronic circular dichroism (ECD) calculations. All isolated compounds were tested for antiviral and anticancer activity.

Evolution-Based Discovery of Polyketide Acylated Valine from a Cytochalasin-Like Gene Cluster in HDN13430.

Utilizing a gene evolution-oriented approach for gene cluster mining, a cryptic cytochalasin-like gene cluster () in Antarctic-derived HDN13430 was identified. Compared with the canonical cytochalasin biosynthetic gene clusters (BGCs), the gene cluster lacks the key α,β-hydrolase gene. Heterologous expression of the gene cluster led to the discovery of a new compound, slamysin (), characterized by an -acylated amino acid structure and demonstrating weak anti- activity.

Cyclo-diphenylalanine production in Aspergillus nidulans through stepwise metabolic engineering.

Cyclo-diphenylalanine (cFF) is a symmetrical aromatic diketopiperazine (DKP) found wide-spread in microbes, plants, and resulting food products. As different bioactivities continue being discovered and relevant food and pharmaceutical applications gradually emerge for cFF, there is a growing need for establishing convenient and efficient methods to access this type of compound. Here, we present a robust cFF production system which entailed stepwise engineering of the filamentous fungal strain Aspergillus nidulans A1145 as a heterologous expression host.

Antibacterial p-terphenyl and α‑pyrone derivates isolated from the marine-derived actinomycete Nocardiopsis sp. HDN154086.

Assisted by OSMAC strategy, one new p-terphenyl and two new α‑pyrone derivates, namely nocarterphenyl I (1) and nocardiopyrone D-E (2-3), were obtained and characterized from the marine sediment-derived actinomycete Nocardiopsis sp. HDN154086. The structures of these compounds were determined on the basis of MS, NMR spectroscopic data and single-crystal X-ray diffraction.

Extending the Structural Diversity of Labdane Diterpenoids from Marine-Derived Fungus sp. HDN151403 Using Heterologous Expression.

Heterologous biosynthesis has become an effective means to activate fungal silent biosynthetic gene clusters (BGCs) and efficiently utilize fungal genetic resources. Herein, thirteen labdane diterpene derivatives, including five undescribed ones named talarobicins A-E (-), were discovered via heterologous expression of a silent BGC () in . Their structures with absolute configurations were elucidated using extensive MS and NMR spectroscopic methods, as well as electronic circular dichroism (ECD) calculations.