Polyketides with α-glucosidase inhibitory and neuroprotective activities from Aspergillus versicolor associated with Pedicularis sylvatica.

Aspergillus versicolor, an endophytic fungus associated with the herbal medicine Pedicularis sylvatica, produced four new polyketides, aspeversins A-D (1-2 and 5-6) and four known compounds, O-methylaverufin (2), aversin (3), varilactone A (7) and spirosorbicillinol A (8). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by calculated electronic circular dichroism (ECD) and Mo2(AcO)4-induced CD data. Compound 5 was found to exhibit α-glucosidase inhibitory activity with an IC50 value of 25.57 µM. An enzyme kinetic study indicated that 5 was a typical uncompetitive inhibitor toward α-glucosidase, which was supported by a molecular docking study. Moreover, compounds 1-3 and 5 also improved the cell viability of PC12 cells on a 1-methyl-4-phenylpyridinium (MPP+)-induced Parkinson's disease model, indicating their neuroprotective potential as antiparkinsonian agents.

Synthesis and Late-Stage Modification of (-)-Doliculide Derivatives Using Matteson's Homologation Approach.

(-)-Doliculide, a marine cyclodepsipeptide derived from the Japanese sea hare, Dolabella auricularia, exhibits potent cytotoxic properties, sparking interest in the field of synthetic chemistry. It is comprised of a peptide segment and a polyketide moiety, rendering it amenable to Matteson's homologation methodology. This technique facilitates the diversification of the distinctive polyketide side chain, thereby permitting the introduction of functional groups in late stages for modifications of the derived compounds and studies on structure-activity relationships.

Genome-guided discovery of two undescribed 6,6-spiroketal polyketides and stereochemical correction of bafilomycins P and Q from the marine-derived Streptomyces sp. SCSIO 66814.

Bafilomycins are macrocyclic polyketides with intriguing structures and therapeutic value. Genomic analysis of Streptomyces sp. SCSIO 66814 revealed a type I polyketide synthase biosynthetic gene cluster (BGC), namely blm, which encoded bafilomycins and featured rich post-modification genes. The One strain many compounds (OSMAC) strategy led to the discovery of six compounds related to the blm BGC from the strain, including two previously undescribed 6,6-spiroketal polyketides, streptospirodienoic acids D (1) and E (2), and four known bafilomycins, bafilomycins P (3), Q (4), D (5), and G (6). The structures of 1 and 2 were determined by extensive spectroscopic analysis, quantum calculation, and biosynthetic analysis. Additionally, the absolute configurations of the 6/5/5 tricyclic ring moiety containing six consecutive chiral carbons in the putative structures of 3 and 4 were corrected through NOE analysis, DP4+ calculation, and single-crystal X-ray diffraction data. Bioinformatic analysis uncovered a plausible biosynthetic pathway for compounds 1-6, indicating that both streptospirodienoic acids and bafilomycins were derived from the same blm BGC. Additionally, sequence analysis revealed that the KR domains of module 2 from blm BGC was B1-type, further supporting the configurations of 1-4. Notably, compounds 3 and 4 displayed significant cytotoxic activities against A-549 human non-small cell lung cancer cells and HCT-116 human colon cancer cells.

Genome Mining of a Deep-Sea-Derived Penicillium allii-sativi Revealed Polyketide-Terpenoid Hybrids with Antiosteoporosis Activity.

Two novel meroterpenoids, alliisativins A and B (1, 2) were discovered through a genome-based exploration of the biosynthetic gene clusters of the deep-sea-derived fungus Penicillium allii-sativi MCCC entry 3A00580. Extensive spectroscopic analysis, quantum calculations, chemical derivatization, and biogenetic considerations were utilized to establish their structures. Alliisativins A and B (1, 2) possess a unique carbon skeleton featuring a drimane sesquiterpene with a highly oxidized polyketide. Noteworthily, alliisativin A (1) showed dual activity in promoting osteogenesis and inhibiting osteoclast, indicating an antiosteoporosis potential.

New meroterpenoids and polyketides from the endophytic fungus Paraphaeosphaeria sp. C-XB-J-1 and their anti-inflammatory and SARS-CoV-2 Mpro inhibitory activities.

Seven new meroterpenoids, paraphaeones A-G (1-7), and two new polyketides, paraphaeones H-I (8-9), along with eight known compounds (10-17), were isolated from the endophytic fungus Paraphaeosphaeria sp. C-XB-J-1. The structures of 1-9 were identified through the analysis of 1H, 13C, and 2D NMR spectra, assisted by HR-ESI-MS data. Compounds 1 and 7 exhibited a dose-dependent decrease in lactate dehydrogenase levels, with IC50 values of 1.78 µM and 1.54 µM, respectively. Moreover, they inhibited the secretion of IL-1ß and CASP-1, resulting in a reduction in the activity levels of NLRP3 inflammasomes. Fluorescence microscopy results indicated that compound 7 concentration-dependently attenuated cell pyroptosis. Additionally, compounds 4 and 7 showed potential inhibitory effects on the severe acute respiratory syndrome coronavirus-2 main protease (SARS-CoV-2 Mpro), with IC50 values of 10.8 ± 0.9 µM and 12.9 ± 0.7 µM, respectively.

Chaetoxylariones A-G: undescribed chromone-derived polyketides from co-culture of Chaetomium virescens and Xylaria grammica enabled via the molecular networking strategy.

By co-culturing two endophytic fungi (Chaetomium virescens and Xylaria grammica) collected from the medicinal and edible plant Smilax glabra Roxb. and analyzing them with MolNetEnhancer module on GNPS platform, seven undescribed chromone-derived polyketides (chaetoxylariones A-G), including three pairs of enantiomer ones (2a/2b, 4a/4b and 6a/6b) and four optical pure ones (1, 3, 5 and 7), as well as five known structural analogues (8-12), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray diffraction, 13C NMR calculation and DP4+ probability analyses, as well as the comparison of the experimental electronic circular dichroism (ECD) data. Structurally, compound 1 featured an unprecedented chromone-derived sulfonamide tailored by two isoleucine-derived δ-hydroxy-3-methylpentenoic acids via the acylamide and NO bonds, respectively; compound 2 represented the first example of enantiomeric chromone derivative bearing a unique spiro-[3.3]alkane ring system; compound 3 featured a decane alkyl side chain that formed an undescribed five-membered lactone ring between C-7' and C-10'; compound 4 contained an unexpected highly oxidized five-membered carbocyclic system featuring rare adjacent keto groups; compound 7 featured a rare methylsulfonyl moiety. In addition, compound 10 showed a significant inhibition towards SW620/AD300 cells with an IC50 value of PTX significantly decreased from 4.09 µM to 120 nM, and a further study uncovered that compound 10 could obviously reverse the MDR of SW620/AD300 cells.

Accraspiroketides A-B, Phenylnaphthacenoid-Derived Polyketides with Unprecedented [6 + 6+6 + 6] + [5 + 5] Spiro-Architecture.

Two novel polyketides, accraspiroketides A (1) and B (2), which feature unprecedented [6 + 6+6 + 6] + [5 + 5] spiro chemical architectures, were isolated from Streptomyces sp. MA37 ΔaccJ mutant strain. Compounds 1-2 exhibit excellent activity against Gram-positive bacteria (MIC = 1.5-6.3 µg/mL). Notably, 1 and 2 have superior activity against clinically isolated Enterococcus faecium K60-39 (MIC = 4.0 µg/mL and 4.7 µg/mL, respectively) than ampicillin (MIC = 25 µg/mL).

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

Utilizing a gene evolution-oriented approach for gene cluster mining, a cryptic cytochalasin-like gene cluster (sla) in Antarctic-derived Simplicillium lamelliciola HDN13430 was identified. Compared with the canonical cytochalasin biosynthetic gene clusters (BGCs), the sla gene cluster lacks the key α,ß-hydrolase gene. Heterologous expression of the sla gene cluster led to the discovery of a new compound, slamysin (1), characterized by an N-acylated amino acid structure and demonstrating weak anti-Bacillus cereus activity. These findings underscore the potential of genetic evolution in uncovering novel compounds and indicating specific adaptive evolution within specialized habitats.

Colibactin-producing Escherichia coli enhance resistance to chemotherapeutic drugs by promoting epithelial to mesenchymal transition and cancer stem cell emergence.

Human colorectal cancers (CRCs) are readily colonized by colibactin-producing E. coli (CoPEC). CoPEC induces DNA double-strand breaks, DNA mutations, genomic instability, and cellular senescence. Infected cells produce a senescence-associated secretory phenotype (SASP), which is involved in the increase in tumorigenesis observed in CRC mouse models infected with CoPEC. This study investigated whether CoPEC, and the SASP derived from CoPEC-infected cells, impacted chemotherapeutic resistance. Human intestinal epithelial cells were infected with the CoPEC clinical 11G5 strain or with its isogenic mutant, which is unable to produce colibactin. Chemotherapeutic resistance was assessed in vitro and in a xenograft mouse model. Expressions of cancer stem cell (CSC) markers in infected cells were investigated. Data were validated using a CRC mouse model and human clinical samples. Both 11G5-infected cells, and uninfected cells incubated with the SASP produced by 11G5-infected cells exhibited an increased resistance to chemotherapeutic drugs in vitro and in vivo. This finding correlated with the induction of the epithelial to mesenchymal transition (EMT), which led to the emergence of cells exhibiting CSC features. They grew on ultra-low attachment plates, formed colonies in soft agar, and overexpressed several CSC markers (e.g. CD133, OCT-3/4, and NANOG). In agreement with these results, murine and human CRC biopsies colonized with CoPEC exhibited higher expression levels of OCT-3/4 and NANOG than biopsies devoid of CoPEC. Conclusion: CoPEC might aggravate CRCs by inducing the emergence of cancer stem cells that are highly resistant to chemotherapy.

A Tricyclic Aromatic Polyketide Isolated from the Marine-Derived Fungus Curvularia aeria.

A novel tricyclic polyketide, curvulanone (1), was isolated from the marine-derived fungus Curvularia aeria. The structure of 1 was determined by NMR and single-crystal X-ray crystallography. 1 had a cyclopentabenzopyranone with 3-acetic acid structure that is rarely found in natural compounds. Monoamine oxidase and sirtuin 1 inhibitory test was exhibited and 1 showed their inhibitory activity.

New Alpiniamide-Type Polyketide with Antibiofilm Activities from the Marine-Derived Streptomyces sp. ZS-A65.

Two new alpiniamide-type polyketides, alpiniamides H-I (1-2), in addition to four recognized compounds, were discovered in Streptomyces sp. ZSA65 derived from the marine sediments. The planar structure and absolute configuration of alpiniamides H-I were elucidated using a combination of 1D, 2D NMR, HRESIMS data analysis, Mosher's method and ECD calculations. The antibiofilm and antibacterial activities against P. aeruginosa were evaluated using the microdilution method. Notably, Compound 2 exhibited strong antibiofilm property.

Aspercitrininone A, novel antibacterial polyketide featuring unusual spiral skeleton from Aspergillus cristatus.

Aspercitrininone A (1), a novel polyketide featuring an unprecedented tetracyclic 6/6/6/5 spiral skeleton, was obtained from the rice fermentation cultures of the fungus Aspergillus cristatus together with five known compounds (2-6). Their structures were determined by HRESIMS data, 1D and 2D NMR spectroscopic analysis, and electronic circular dichroism (ECD) calculations. Aspercitrininone A was revealed as a new type of C/D cycle spiral structure and an unusual addition product of o-quinoid form citrinin with 2-methylterrefuranone. Compounds 1, 4, and 5 exhibited potent antibacterial activities with minimal inhibitory concentration (MIC) values from 13.2 to 67.3 µg/mL against four strains of human pathogenic bacteria in vitro.

Antibiofilm activity of marine microbial natural products: potential peptide- and polyketide-derived molecules from marine microbes toward targeting biofilm-forming pathogens.

Controlling and treating biofilm-related infections is challenging because of the widespread presence of multidrug-resistant microbes. Biofilm, a naturally occurring matrix of microbial aggregates, has developed intricate and diverse resistance mechanisms against many currently used antibiotics. This poses a significant problem, especially for human health, including clinically chronic infectious diseases. Thus, there is an urgent need to search for and develop new and more effective antibiotics. As the marine environment is recognized as a promising reservoir of new biologically active molecules with potential pharmacological properties, marine natural products, particularly those of microbial origin, have emerged as a promising source of antibiofilm agents. Marine microbes represent an untapped source of secondary metabolites with antimicrobial activity. Furthermore, marine natural products, owing to their self-defense mechanisms and adaptation to harsh conditions, encompass a wide range of chemical compounds, including peptides and polyketides, which are primarily found in microbes. These molecules can be exploited to provide novel and unique structures for developing alternative antibiotics as effective antibiofilm agents. This review focuses on the possible antibiofilm mechanism of these marine microbial molecules against biofilm-forming pathogens. It provides an overview of biofilm development, its recalcitrant mode of action, strategies for the development of antibiofilm agents, and their assessments. The review also revisits some selected peptides and polyketides from marine microbes reported between 2016 and 2023, highlighting their moderate and considerable antibiofilm activities. Moreover, their antibiofilm mechanisms, such as adhesion modulation/inhibition targeting biofilm-forming pathogens, quorum sensing intervention and inhibition, and extracellular polymeric substance disruption, are highlighted herein.

Antifeedant, Antifungal Cryptic Polyketides with Six Structural Frameworks from Tea Endophyte Daldinia eschscholtzii Propelled by the Antagonistic Coculture with Phytopathogen Colletotrichum pseudomajus and Different Culture Methods.

The antagonistic coculture with tea phytopathogen Colletotrichum pseudomajus induces antifungal cryptic metabolites from isogenesis endophyte Daldinia eschscholtzii against tea phytopathogens. Sixteen new polyketides with six structural frameworks including ten cryptic ones, named coldaldols A-C (1-3), collediol (5), and daldinrins A-L (10-20 and 23), were found from the coculture of C. pseudomajus and D. eschscholtzii by different culture methods. The unique framework of compounds 11 and 12 featured a benzopyran-C7 polyketone hybrid, and compounds 13-16 were characterized by the novel benzopyran dimer. The structures were determined mainly by spectroscopic methods, including extensive one-dimensional (1D), two-dimensional (2D) NMR, high resolution electrospray ionisation mass spectroscopy (HRESIMS), ECD calculation, and single-crystal X-ray diffraction. The configuration of acyclic compounds 5 and 18 were determined by application of the universal NMR database. Most compounds showed significant antifungal activities against the tea pathogens C. pseudomajus and Alternaria sp. with MICs of 1-8 µg/mL. Compound 12 had stronger antifungal activity than that of positive drug nystatin. The ether bond at C-4 of the benzopyran derivative increased the antifungal activity. Compounds 4-9 and 11-23 showed antifeedant activities against silkworms with feeding deterrence indices of 15-100% at the concentration of 50 µg/cm2.

Characterization of Bacillus velezensis 32a metabolites and their synergistic bioactivity against crown gall disease.

Crown gall disease caused by Agrobacterium tumefaciens is considered to be the main bacterial threat of stone fruit plants in Mediterranean countries. In a previous study, Bacillus velezensis strain 32a was isolated from Tunisian rhizosphere soil and revealed high antagonistic potential against A. tumefaciens strains. In order to better characterize the antagonistic activity of this strain against this important plant pathogen, the production of secondary metabolites was analyzed using liquid chromatography coupled with mass spectrometry. The results revealed the production of different compounds identified as surfactins, fengycins, iturins and bacillibactin belonging to the lipopeptide group, three polyketides (macrolactins, oxydifficidin and bacillaenes), bacilysin and its chlorinated derivative; chlorotetaine. The involvement of lipopeptides in this antagonistic activity was ruled out by performing agar and broth dilution tests with pure molecules. Thus, the construction of B. velezensis 32a mutants defective in polyketides and bacilysin biosynthesis and their antagonistic activity was performed and compared to a set of derivative mutants of a comparable strain, B. velezensis GA1. The defective difficidin mutants (△dfnA and △dfnD) were unable to inhibit the growth of A. tumefaciens, indicating the high-level contribution of difficidin in the antagonism process. While the macrolactin deficient mutant (∆mlnA) slightly decreased the activity, suggesting a synergetic effect with difficidin. Remarkably, the mutant △dhbC only deficient in bacillibactin production showed significant reduction in its capacity to inhibit the growth of Agrobacterium.Taken collectively, our results showed the strong synergetic effect of difficidin and macrolactins and the significant implication of siderophore to manage crown gall disease.

Diaphorin, a polyketide produced by a bacterial endosymbiont of the Asian citrus psyllid, adversely affects the in vitro gene expression with ribosomes from Escherichia coli and Bacillus subtilis.

Diaphorin is a polyketide produced by "Candidatus Profftella armatura" (Gammaproteobacteria), an obligate mutualist of an important agricultural pest, the Asian citrus psyllid Diaphorina citri (Hemiptera). Our previous study demonstrated that diaphorin, at physiological concentrations in D. citri, inhibits the growth and cell division of Bacillus subtilis (Firmicutes) but promotes the growth and metabolic activity of Escherichia coli (Gammaproteobacteria). This unique property of diaphorin may aid microbial mutualism in D. citri, potentially affecting the transmission of "Candidatus Liberibacter spp." (Alphaproteobacteria), the pathogens of the most destructive citrus disease Huanglongbing. Moreover, this property may be exploited to promote microbes' efficiency in producing industrial materials. However, the mechanism underlying this activity is unknown. Diaphorin belongs to the family of pederin-type compounds, which inhibit protein synthesis in eukaryotes by binding to eukaryotic ribosomes. Therefore, as a first step to assess diaphorin's direct influence on bacterial gene expression, this study examined the effect of diaphorin on the in vitro translation using ribosomes of B. subtilis and E. coli, quantifying the production of the green fluorescent protein. The results showed that the gene expression involving B. subtilis and E. coli ribosomes along with five millimolar diaphorin was 29.6% and 13.1%, respectively, less active than the control. This suggests that the diaphorin's adverse effects on B. subtilis are attributed to, at least partly, its inhibitory effects on gene expression. Moreover, as ingredients of the translation system were common other than ribosomes, the greater inhibitory effects observed with the B. subtilis ribosome imply that the ribosome is among the potential targets of diaphorin. On the other hand, the results also imply that diaphorin's positive effects on E. coli are due to targets other than the core machinery of transcription and translation. This study demonstrated for the first time that a pederin congener affects bacterial gene expression.

Natural Polyketides Act as Promising Antifungal Agents.

Invasive fungal infections present a significant risk to human health. The current arsenal of antifungal drugs is hindered by drug resistance, limited antifungal range, inadequate safety profiles, and low oral bioavailability. Consequently, there is an urgent imperative to develop novel antifungal medications for clinical application. This comprehensive review provides a summary of the antifungal properties and mechanisms exhibited by natural polyketides, encompassing macrolide polyethers, polyether polyketides, xanthone polyketides, linear polyketides, hybrid polyketide non-ribosomal peptides, and pyridine derivatives. Investigating natural polyketide compounds and their derivatives has demonstrated their remarkable efficacy and promising clinical application as antifungal agents.

New Cyclopiane Diterpenes and Polyketide Derivatives from Marine Sediment-Derived Fungus Penicillium antarcticum KMM 4670 and Their Biological Activities.

Two new cyclopiane diterpenes and a new cladosporin precursor, together with four known related compounds, were isolated from the marine sediment-derived fungus Penicillium antarcticum KMM 4670, which was re-identified based on phylogenetic inference from ITS, BenA, CaM, and RPB2 gene regions. The absolute stereostructures of the isolated cyclopianes were determined using modified Mosher's method and quantum chemical calculations of the ECD spectra. The isolation from the natural source of two biosynthetic precursors of cladosporin from a natural source has been reported for the first time. The antimicrobial activities of the isolated compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans as well as the inhibition of staphylococcal sortase A activity were investigated. Moreover, the cytotoxicity of the compounds to mammalian cardiomyocytes H9c2 was studied. As a result, new cyclopiane diterpene 13-epi-conidiogenone F was found to be a sortase A inhibitor and a promising anti-staphylococcal agent.

Advances on structure, bioactivity, and biosynthesis of amino acid-containing trans-AT polyketides.

Trans-AT polyketides represent a class of natural compounds utilizing independent acyltransferase during their biosynthesis. They are well known for their diverse chemical structures and potent bioactivities. Trans-AT polyketides are synthesized through biosynthetic gene clusters predominantly composed of polyketide synthases (PKS), but often found in hybrid with non-ribosomal peptide synthetases (NRPS). This genetic hybridization results in the incorporation of amino acid residues into polyketide structures, significantly enhancing their structural diversity. Numerous amino acid-containing trans-AT polyketides have been identified, drawing significant attention to the mechanisms underlying amino acid incorporation and their impact on the biological activity of polyketides. Here, we discussed their origins, structures, biological activities, and the specific roles of amino acids in modulating both the bioactivity and biosynthesis of 38 trans-AT polyketides containing amino acids for the first time. This comprehensive analysis will serve as a crucial reference for the exploration of novel compounds and the improvement of structures and activities.

Induction of New Aromatic Polyketides from the Marine Actinobacterium Streptomyces griseorubiginosus through an OSMAC Approach.

Using the OSMAC (One Strain Many Compounds) approach, the actinobacterium Streptomyces griseorubiginosus, derived from an unidentified cnidarian collected from a reef near Pointe de Bellevue in Réunion Island (France), was subjected to cultivation under diverse conditions. This endeavour yielded the isolation of a repertoire of 23 secondary metabolites (1-23), wherein five compounds were unprecedented as natural products (19-23). Specifically, compounds 19 and 20 showcased novel anthrone backbones, while compound 23 displayed a distinctive tetralone structure. Additionally, compounds 21 and 22 presented an unusual naphtho [2,3-c]furan-4(9H)-one chromophore. Interestingly, the detection of all these novel compounds (19-23) was exclusively achieved when the bacterium was cultured in FA-1 liquid medium supplemented with the epigenetic modifier γ-butyrolactone. The elucidation of the structural features of the newfound compounds was accomplished through a combination of HRESIMS, 1D and 2D NMR spectroscopy, as well as QM-NMR (Quantum Mechanical-Nuclear Magnetic Resonance) methods and by comparison with existing literature. Moreover, the determination of the relative configuration of compound 23 was facilitated by employing the mix-J-DP4 computational approach.