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The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find new candidates that target viral proteins with a clear in vitro and in vivo phenotype. Mpro (or 3CLpro) is directly involved in the viral replication cycle and the production and function of viral polyproteins, which makes it an ideal target. The biological relevance of Mpro is highly conserved among betacoronaviruses like HCoV-OC43 and SARS-CoV-2, which makes the identification of new chemical scaffolds targeting them a good starting point for designing broad-spectrum antivirals. We report an optimized methodology based on orthogonal cell-free assays to identify small molecules that inhibit the binding pockets of both SARS-CoV-2-Mpro and HCoV-OC43-Mpro; this blockade correlates with antiviral activities in HCoV-OC43 cellular models. By using such a fast-tracking approach against the Open Global Health Library (Merck KGaA), we have found evidence of the antiviral activity of compound OGHL98. In silico studies dissecting intermolecular interactions between OGHL98 and both proteases and comprising docking and molecular dynamics simulations (MDSs) concluded that the binding mode was primarily governed by conserved H-bonds with their C-terminal amino acids and that the rational design of OGHL98 has potential against VoCs proteases resistant to current therapeutics.
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A study targeting novel antifungal metabolites identified potent in vitro antifungal activity against key plant pathogens in acetone extracts of Streptomyces sp. strain CA-296093. Feature-based molecular networking revealed the presence in this extract of antimycin-related compounds, leading to the isolation of four new compounds: escuzarmycins A-D (1-4). Extensive structural elucidation, employing 1D and 2D NMR, high-resolution mass spectrometry, Marfey's analysis, and NOESY correlations, confirmed their structures. The bioactivity of these compounds was tested against six fungal phytopathogens, and compounds 3 and 4 demonstrated strong efficacy, particularly against Zymoseptoria tritici, with compound 3 exhibiting the highest potency (EC50: 11 nM). Both compounds also displayed significant antifungal activity against Botrytis cinerea and Colletotrichum acutatum, with compound 4 proving to be the most potent. Despite moderate cytotoxicity against the human cancer cell line HepG2, compounds 3 and 4 emerge as promising fungicides for combating Septoria tritici blotch, anthracnose, and gray mold.
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Ascomicetos , Colletotrichum , Fungicidas Industriales , Enfermedades de las Plantas , Streptomyces , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Ascomicetos/efectos de los fármacos , Ascomicetos/química , Streptomyces/química , Streptomyces/metabolismo , Humanos , Colletotrichum/efectos de los fármacos , Botrytis/efectos de los fármacos , Estructura MolecularRESUMEN
Pancreatic cancer (PC) shows a high fatality rate that can only be faced with a combination of surgery and chemotherapy or palliative treatment in the case of advanced patients. Besides, PC tumors are enriched with subpopulations of cancer stem cells (CSCs) that are resistant to the existing chemotherapeutic agents, which raises an important need for the identification of new drugs. To fill this gap, we have tested the anti-tumoral activity of microbial extracts, which chemical diversity offers a broad spectrum of potential new bioactive compounds. Extracts derived from the fungus Onychocola sp. CF-107644 were assayed via high throughput screening followed by bioassay-guided fractionation and resulted in the identification and isolation of six benzophenone derivatives with antitumoral activity: onychocolones A-F (#1-6). The structures of the compounds were established by spectroscopic methods, including ESI-TOF MS, 1D and 2D NMR analyses and X-ray diffraction. Compounds #1-4 significantly inhibited the growth of the pancreas tumoral cell lines, with low-micromolar Median Effective Doses (ED50s). Compound #1 (onychocolone A) was prioritized for further profiling due to its pro-apoptotic effect, which was further validated on 3D spheroids and pancreatic CSCs. Protein expression assays showed that the effect was mechanistically linked to the inhibition of MEK onco-signaling pathway. The efficacy of onychocolone A was also demonstrated in vivo by the reduction of tumor growth in a pancreatic xenograft mouse model generated by CSCs. Altogether, the data support that onychocolone A is a promising new small molecule for hit-to-lead development of a new treatment for PC.
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Antineoplásicos , Células Madre Neoplásicas , Neoplasias Pancreáticas , Transducción de Señal , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Animales , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Ratones , Antineoplásicos/farmacología , Benzofenonas/farmacología , Benzofenonas/química , Ensayos Antitumor por Modelo de Xenoinjerto , Ascomicetos/química , Ratones Desnudos , Proliferación Celular/efectos de los fármacosRESUMEN
Genome analysis of strain Streptomyces sp. CA-278952 revealed a biosynthetic gene cluster encoding a putative lipopeptide with a sequence containing an Asp-Gly-Glu-Ala motif. We envisioned that this motif could mimic the canonical Asp-X-Asp-Gly sequence found in previously reported calcium-dependent lipopeptide antibiotics. Chemical investigation of the producing strain led to the discovery of three novel lipodepsipeptides, dilarmycins A-C. The calcium-dependent antibacterial activity of the new compounds was confirmed against the Gram-positive pathogens methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus.
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Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Antibacterianos/farmacología , Antibacterianos/química , Calcio , Lipopéptidos/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
The PD-1/PD-L1 protein-protein interaction (PPI) controls an adaptive immune resistance mechanism exerted by tumor cells to evade immune responses. The large-molecule nature of current commercial monoclonal antibodies against this PPI hampers their effectiveness by limiting tumor penetration and inducing severe immune-related side effects. Synthetic small-molecule inhibitors may overcome such limitations and have demonstrated promising clinical translation, but their design is challenging. Microbial natural products (NPs) are a source of small molecules with vast chemical diversity that have proved anti-tumoral activities, but which immunotherapeutic properties as PD-1/PD-L1 inhibitors had remained uncharacterized so far. Here, we have developed the first cell-based PD-1/PD-L1 blockade reporter assay to screen NPs libraries. In this study, 6000 microbial extracts of maximum biosynthetic diversity were screened. A secondary metabolite called alpha-cyclopiazonic acid (α-CPA) of a bioactive fungal extract was confirmed as a new PD-1/PD-L1 inhibitor with low micromolar range in the cellular assay and in an additional cell-free competitive assay. Thermal denaturation experiments with PD-1 confirmed that the mechanism of inhibition is based on its stabilization upon binding to α-CPA. The identification of α-CPA as a novel PD-1 stabilizer proves the unprecedented resolution of this methodology at capturing specific PD-1/PD-L1 PPI inhibitors from chemically diverse NP libraries.
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Antígeno B7-H1 , Neoplasias , Humanos , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Anticuerpos MonoclonalesRESUMEN
Cancer is one of the leading causes of death worldwide, with breast cancer being the second cause of cancer-related mortality among women. Natural Products (NPs) are one of the main sources for drug discovery. During a screening campaign focused on the identification of extracts from Fundación MEDINA's library inhibiting the proliferation of cancer cell lines, a significant bioactivity was observed in extracts from cultures of the fungus Angustimassarina populi CF-097565. Bioassay-guided fractionation of this extract led to the identification and isolation of herbarin (1), 1-hydroxydehydroherbarin (4) plus other three naphthoquinone derivatives of which 3 and 5 are new natural products and 2 is herein described from a natural source for the first time. Four of these compounds (1, 3, 4 and 5) confirmed a specific cytotoxic effect against the human breast cancer cell line MCF-7. To evaluate the therapeutic potential of the compounds isolated, their efficacy was validated in 3D cultures, a cancer model of higher functionality. Additionally, an in-depth study was carried out to test the effect of the compounds in terms of cell mortality, sphere disaggregation, shrinkage, and morphology. The cell profile of the compounds was also compared to that of known cytotoxic compounds with the aim to distinguish the drug mode of action (MoA). The profiles of 1, 3 and 4 showed more biosimilarity between them, different to 5, and even more different to other known cytotoxic agents, suggesting an alternative MoA responsible for their cytotoxicity in 3D cultures.
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Ascomicetos , Biosimilares Farmacéuticos , Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , BioensayoRESUMEN
IMPORTANCE: The COVID-19 pandemic has revealed the lack of effective treatments against betacoronaviruses and the urgent need for new broad-spectrum antivirals. Natural products are a valuable source of bioactive compounds with pharmaceutical potential that may lead to the discovery of new antiviral agents. Specifically, compared to conventional synthetic molecules, microbial natural extracts possess a unique and vast chemical diversity and are amenable to large-scale production. The implementation of a high-throughput screening platform using the betacoronavirus OC43 in a human cell line infection model has provided proof of concept of the approach and has allowed for the rapid and efficient evaluation of 1,280 microbial extracts. The identification of several active compounds validates the potential of the platform for the search for new compounds with antiviral capacity.
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Productos Biológicos , Coronavirus Humano OC43 , Humanos , Productos Biológicos/farmacología , Productos Biológicos/metabolismo , Pandemias , Línea Celular , Antivirales/farmacologíaRESUMEN
Duchenne muscular dystrophy (DMD) is a devastating degenerative disease of skeletal muscles caused by loss of dystrophin, a key protein that maintains muscle integrity, which leads to progressive muscle degeneration aggravated by chronic inflammation, muscle stem cells' (MuSCs) reduced regenerative capacity and replacement of muscle with fibroadipose tissue. Previous research has shown that pharmacological GSK-3ß inhibition favors myogenic differentiation and plays an important role in modulating inflammatory processes. Isolecanoric acid (ILA) is a natural product isolated from a fungal culture displaying GSK-3ß inhibitory properties. The present study aimed to investigate the proregenerative and anti-inflammatory properties of this natural compound in the DMD context. Our results showed that ILA markedly promotes myogenic differentiation of myoblasts by increasing ß-Catenin signaling and boosting the myogenic potential of mouse and human stem cells. One important finding was that the GSK-3ß/ß-Catenin pathway is altered in dystrophic mice muscle and ILA enhances the myofiber formation of dystrophic MuSCs. Treatment with this natural compound improves muscle regeneration of dystrophic mice by, in turn, improving functional performance. Moreover, ILA ameliorates the inflammatory response in both muscle explants and the macrophages isolated from dystrophic mice to, thus, mitigate fibrosis after muscle damage. Overall, we show that ILA modulates both inflammation and muscle regeneration to, thus, contribute to improve the dystrophic phenotype.
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Distrofia Muscular de Duchenne , Animales , Ratones , Humanos , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/metabolismo , beta Catenina/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Ratones Endogámicos mdx , Músculo Esquelético , Inflamación/metabolismo , Modelos Animales de EnfermedadRESUMEN
The co-culturing of microorganisms is a well-known strategy to study microbial interactions in the laboratory. This approach facilitates the identification of new signals and molecules produced by one species that affects other species' behavior. In this work, we have studied the effects of the interaction of nine Streptomyces species (S. albidoflavus, S. ambofaciens, S. argillaceus, S. griseus, S. lividans, S. olivaceus, S. parvulus, S. peucetius, and S. rochei) with the predator bacteria Myxococcus xanthus, five of which (S. albidoflavus, S. griseus, S. lividans, S. olivaceus, and S. argillaceus) induce mound formation of M. xanthus on complex media (Casitone Yeast extract (CYE) and Casitone tris (CTT); media on which M. xanthus does not form these aggregates under normal culture conditions. An in-depth study on S. griseus-M. xanthus interactions (the Streptomyces strain producing the strongest effect) has allowed the identification of two siderophores produced by S. griseus, demethylenenocardamine and nocardamine, responsible for this grouping effect over M. xanthus. Experiments using pure commercial nocardamine and different concentrations of FeSO4 show that iron depletion is responsible for the behavior of M. xanthus. Additionally, it was found that molecules, smaller than 3 kDa, produced by S. peucetius can induce the production of DK-xanthenes by M. xanthus.
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Myxococcus xanthus , Myxococcus , Streptomyces , Interacciones Microbianas , HierroRESUMEN
Natural Products (NPs) are one of the main sources for drug discovery. Many clinical drugs are NPs or NP-inspired compounds, and recently discovered New Chemical Entities (NCEs) of NPs are emerging as promising new drugs. High-Throughput Screening (HTS) of large sample sets or libraries has grown to be vital for the drug discovery field. Industrial-scale HTS of NP libraries can be limited due to the difficulties entailed in working with tiny extract volumes and the variability in viscosity of NP extracts. For these reasons, the implementation of new technologies to miniaturize different reagent volumes grows to be fundamental. Since Acoustic Droplet Ejection (ADE) emerged as a helpful tool in HTS campaigns for the transference of compound libraries. The aim of this work was to test the effectiveness of ADE for the dispensation of NP extract libraries in cell-based HTS assays.
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Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer's disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson's disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.
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Fungal phytopathogens are the major agents responsible for causing severe damage to and losses in agricultural crops worldwide. Botrytis cinerea, Colletotrichum acutatum, Fusarium proliferatum, and Magnaporthe grisea are included in the top ten fungal phytopathogens that impose important plant diseases on a broad range of crops. Microbial natural products can be an attractive alternative for the biological control of phytopathogens. The objective of this work was to develop and validate a High-throughput Screening (HTS) platform to evaluate the antifungal potential of chemicals and natural products against these four important plant pathogens. Several experiments were performed to establish the optimal assay conditions that provide the best reproducibility and robustness. For this purpose, we have evaluated two media formulations (SDB and RPMI-1640), several inoculum concentrations (1 × 106, 5 × 105 and 5 × 106 conidia/mL), the germination curves for each strain, each strain's tolerance to dimethyl sulfoxide (DMSO), and the Dose Response Curves (DRC) of the antifungal control (Amphotericin B). The assays were performed in 96-well plate format, where absorbance at 620 nm was measured before and after incubation to evaluate growth inhibition, and fluorescence intensity at 570 nm excitation and 615 nm emission was monitored after resazurin addition for cell viability evaluation. Quality control parameters (RZ' Factors and Signal to Background (S/B) ratios) were determined for each assay batch. The assay conditions were finally validated by titrating 40 known relevant antifungal agents and testing 2400 microbial natural product extracts from the MEDINA Library through both HTS agar-based and HTS microdilution-based set-ups on the four phytopathogens.
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In a survey to evaluate the potential of lichens associated with gypsum areas as sources of new antifungal metabolites, six species of lichens were collected in the gypsum outcrops of the Sorbas Desert (Diploschistes ocellatus and Seirophora lacunosa) and the Tabernas Desert (Cladonia foliacea, Acarospora placodiformis, Squamarina lentigera and Xanthoparmelia pokornyi) in southern Spain. Raw lichen acetone extracts were tested against a panel of seven phytopathogenic fungi, including Botrytis cinerea, Colletotrichum acutatum, Fusarium oxysporum f.sp cubense TR4, Fusarium ploriferaum, Magnaporthe grisea, Verticillium dahliae and Zymoseptoria tritici. Active extracts of Cladonia foliacea, Xanthoparmelia pokornyi and Squamarina lentigera were analyzed by HPLC-MS/MS and Molecular Networking to identify possible metabolites responsible for the antifungal activity. A total of ten depside-like metabolites were identified by MS/MS dereplication and NMR experiments, of which one was a new derivative of fumaroprotocetraric acid. The compounds without previously described biological activity were purified and tested against the panel of fungal phytopathogens. Herein, the antifungal activity against fungal phytopathogens of 4'-O-methylpaludosic acid, divaricatic acid and stenosporic acid is reported for the first time. Stenosporic and divaricatic acids displayed a broad antifungal spectrum against seven relevant fungal phytopathogens in a micromolar range, including the extremely resistant fungus F. oxysporum f. sp. cubense Tropical Race 4 (TR4). 4'-O-methylpaludosic acid exhibited specific antifungal activity against the wheat pathogen Z. tritici, with an IC50 of 38.87 µg/mL (87.1 µM) in the absorbance-based assay and 24.88 µg/mL (55.52 µM) in the fluorescence-based assay.
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Neglected diseases caused by kinetoplastid parasites are a health burden in tropical and subtropical countries. The need to create safe and effective medicines to improve treatment remains a priority. Microbial natural products are a source of chemical diversity that provides a valuable approach for identifying new drug candidates. We recently reported the discovery and bioassay-guided isolation of a novel family of macrolides with antiplasmodial activity. The novel family of four potent antimalarial macrolides, strasseriolides A-D, was isolated from cultures of Strasseria geniculata CF-247251, a fungal strain obtained from plant tissues. In the present study, we analyze these strasseriolides for activity against kinetoplastid protozoan parasites, namely, Trypanosoma brucei brucei, Leishmania donovani and Trypanosoma cruzi. Compounds exhibited mostly low activities against T. b. brucei, yet notable growth inhibition and selectivity were observed for strasseriolides C and D in the clinically relevant intracellular T. cruzi and L. donovani amastigotes with EC50 values in the low micromolar range. Compound C is fast-acting and active against both intracellular and trypomastigote forms of T. cruzi. While cell cycle defects were not identified, prominent morphological changes were visualized by differential interference contrast microscopy and smaller and rounded parasites were visualized upon exposure to strasseriolide C. Moreover, compound C lowers parasitaemia in vivo in acute models of infection of Chagas disease. Hence, strasseriolide C is a novel natural product active against different forms of T. cruzi in vitro and in vivo. The study provides an avenue for blocking infection of new cells, a strategy that could additionally contribute to avoid treatment failure.
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Enfermedad de Chagas , Parásitos , Trypanosoma brucei brucei , Trypanosoma cruzi , Animales , Enfermedad de Chagas/tratamiento farmacológico , Macrólidos/farmacologíaRESUMEN
Antimicrobial resistance can be considered a hidden global pandemic and research must be reinforced for the discovery of new antibiotics. The spirotetronate class of polyketides, with more than 100 bioactive compounds described to date, has recently grown with the discovery of phocoenamicins, compounds displaying different antibiotic activities. Three marine Micromonospora strains (CA-214671, CA-214658 and CA-218877), identified as phocoenamicins producers, were chosen to scale up their production and LC/HRMS analyses proved that EtOAc extracts from their culture broths produce several structurally related compounds not disclosed before. Herein, we report the production, isolation and structural elucidation of two new phocoenamicins, phocoenamicins D and E (1-2), along with the known phocoenamicin, phocoenamicins B and C (3-5), as well as maklamicin (7) and maklamicin B (6), the latter being reported for the first time as a natural product. All the isolated compounds were tested against various human pathogens and revealed diverse strong to negligible activity against methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis H37Ra, Enterococcus faecium and Enterococcus faecalis. Their cell viability was also evaluated against the human liver adenocarcinoma cell line (Hep G2), demonstrating weak or no cytotoxicity. Lastly, the safety of the major compounds obtained, phocoenamicin (3), phocoenamicin B (4) and maklamicin (7), was tested against zebrafish eleuthero embryos and all of them displayed no toxicity up to a concentration of 25 µM.
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Staphylococcus aureus Resistente a Meticilina , Micromonospora , Humanos , Animales , Pez Cebra , Macrólidos/farmacología , Antibacterianos/farmacologíaRESUMEN
Crosiellidines are intriguing pyrazine-alkylguanidine metabolites isolated from the minor actinomycete genus Crossiella. Their structures present an unprecedented 2-methoxy-3,5,6-trialkyl pyrazine scaffold and uncommon guanidine prenylations, including an exotic O-prenylated N-hydroxyguanidine moiety. The novel substitution pattern of the 2-methoxypyrazine core inaugurates a new class of naturally occurring pyrazine compounds, the biosynthetic implications of which are discussed herein. Isotopic feeding and genome analysis allowed us to propose a biosynthetic pathway from arginine. The crossiellidines exhibited remarkable, broad-spectrum antibacterial activity.
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Actinobacteria , Actinomycetales , Pirazinas/farmacología , Actinomycetales/química , Actinobacteria/química , Antibacterianos/química , Vías BiosintéticasRESUMEN
Antibiotic resistance is reaching alarming levels, demanding for the discovery and development of antibiotics with novel chemistry and mechanisms of action. The recently discovered antibiotic cacaoidin combines the characteristic lanthionine residue of lanthipeptides and the linaridin-specific N-terminal dimethylation in an unprecedented N-dimethyl lanthionine ring, being therefore designated as the first class V lanthipeptide (lanthidin). Further notable features include the high D-amino acid content and a unique disaccharide substitution attached to the tyrosine residue. Cacaoidin shows antimicrobial activity against gram-positive pathogens and was shown to interfere with peptidoglycan biosynthesis. Initial investigations indicated an interaction with the peptidoglycan precursor lipid IIPGN as described for several lanthipeptides. Using a combination of biochemical and molecular interaction studies we provide evidence that cacaoidin is the first natural product demonstrated to exhibit a dual mode of action combining binding to lipid IIPGN and direct inhibition of cell wall transglycosylases.
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Minor genera actinomycetes are considered a promising source of new secondary metabolites. The strain Kribbella sp. CA-293567 produces sandramycin and kribbellichelins A & B In this work, we describe the complete genome sequencing of this strain and the in silico identification of biosynthetic gene clusters (BGCs), focusing on the pathways encoding sandramycin and kribbellichelins A-B. We also present a comparative analysis of the biosynthetic potential of 38 publicly available genomes from Kribbella strains.
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Globomycin is a cyclic lipodepsipeptide originally isolated from several Streptomyces species which displays strong and selective antibacterial activity against Gram-negative pathogens. Its mode of action is based on the competitive inhibition of the lipoprotein signal peptidase II (LspA), which is absent in eukaryotes and considered an attractive target for the development of new antibiotics. Despite its interesting biological properties, the gene cluster encoding its biosynthesis has not yet been identified. In this study we employed a genome-mining approach in the globomycin-producing Streptomyces sp. CA-278952 to identify a candidate gene cluster responsible for its biosynthesis. A null mutant was constructed using CRISPR base editing where production was abolished, strongly suggesting its involvement in the biosynthesis. The putative gene cluster was then cloned and heterologously expressed in Streptomyces albus J1074 and Streptomyces coelicolor M1146, therefore unambiguously linking globomycin and its biosynthetic gene cluster. Our work paves the way for the biosynthesis of new globomycin derivatives with improved pharmacological properties.
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Memnoniella is a fungal genus from which a wide range of diverse biologically active compounds have been isolated. A Memnoniella dichroa CF-080171 extract was identified to exhibit potent activity against Plasmodium falciparum 3D7 and Trypanosoma cruzi Tulahuen whole parasites in a high-throughput screening (HTS) campaign of microbial extracts from the Fundación MEDINA's collection. Bioassay-guided isolation of the active metabolites from this extract afforded eight new meroterpenoids of varying potencies, namely, memnobotrins C-E (1-3), a glycosylated isobenzofuranone (4), a tricyclic isobenzofuranone (5), a tetracyclic benzopyrane (6), a tetracyclic isobenzofuranone (7), and a pentacyclic isobenzofuranone (8). The structures of the isolated compounds were established by (+)-ESI-TOF high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Compounds 1, 2, and 4 exhibited potent antiparasitic activity against P. falciparum 3D7 (EC50 0.04-0.243 µM) and T. cruzi Tulahuen (EC50 0.266-1.37 µM) parasites, as well as cytotoxic activity against HepG2 tumoral liver cells (EC50 1.20-4.84 µM). The remaining compounds (3, 5-8) showed moderate or no activity against the above-mentioned parasites and cells.