Modulation of the Meisenheimer complex metabolism of nitro-benzothiazinones by targeted C-6 substitution.

Tuberculosis, caused by Mycobacterium tuberculosis, remains a major public health concern, demanding new antibiotics with innovative therapeutic principles due to the emergence of resistant strains. Benzothiazinones (BTZs) have been developed to address this problem. However, an unprecedented in vivo biotransformation of BTZs to hydride-Meisenheimer complexes has recently been discovered.

Whole cell hydride Meisenheimer complex biotransformation guided optimization of antimycobacterial benzothiazinones.

Nitrobenzothiazinones (BTZs) are potent active substances against Mycobacterium tuberculosis with currently two investigational drugs in clinical development for the treatment of tuberculosis. BTZs are the first examples for which a metabolic pathway towards transient hydride Meisenheimer complexes (HMC) has been shown in mammals, including humans. In this study, lead optimization efforts on BTZs are guided by the systematic evaluation of the HMC formation propensity combined with multiparameter assessment.

Discovery and Biosynthesis of the Cytotoxic Polyene Terpenomycin in Human Pathogenic .

are opportunistic human pathogens that can cause a range of debilitating and difficult to treat infections of the lungs, brain, skin, and soft tissues. Despite their close relationship to the well-known secondary metabolite-producing genus, , comparatively few natural products are known from the , and even less is known about their involvement in the pathogenesis. Here, we combine chemistry, genomics, and molecular microbiology to reveal the production of terpenomycin, a new cytotoxic and antifungal polyene from a human pathogenic isolate.

Natural products from reconstructed bacterial genomes of the Middle and Upper Paleolithic.

Major advances over the past decade in the field of ancient DNA are providing access to past paleogenomic diversity, but the diverse functions and biosynthetic capabilities of this growing paleome remain largely elusive. We investigated the dental calculus of 12 Neanderthals and 52 anatomically modern humans ranging from 100,000 years ago to the present and reconstructed 459 bacterial metagenome-assembled genomes. We identified a biosynthetic gene cluster shared by seven Middle and Upper Paleolithic individuals that allows for the heterologous production of a class of previously unknown metabolites that we name "paleofurans.

Ecological Niche-Inspired Genome Mining Leads to the Discovery of Crop-Protecting Nonribosomal Lipopeptides Featuring a Transient Amino Acid Building Block.

Investigating the ecological context of microbial predator-prey interactions enables the identification of microorganisms, which produce multiple secondary metabolites to evade predation or to kill the predator. In addition, genome mining combined with molecular biology methods can be used to identify further biosynthetic gene clusters that yield new antimicrobials to fight the antimicrobial crisis. In contrast, classical screening-based approaches have limitations since they do not aim to unlock the entire biosynthetic potential of a given organism.

Precursor-Directed Synthesis of Apoptosis-Initiating N-Hydroxyalkyl Phenylbenzoisoquinolindione Alkaloids.

A precursor-directed approach to access N-hydroxyalkyl phenylbenzoisoquinolindiones (PBIQs) has been developed. Incubation of plant material of Xiphidium caeruleum with hydroxylamines of various chain lengths (C , C , C , C , C and C ) resulted in 11 new 5-hydroxy- and 5-methoxy PBIQs with different N-hydroxyalkyl side chain lengths. The antiproliferative effect and the cytotoxicity against HUVEC, K-562, and HeLa cell lines of 26 previously reported PBIQs and the 11 newly synthesized N-hydroxyalkyl PBIQs was determined for the first time.

Antiproliferative and Cytotoxic Cytochalasins from Inhibit Actin Polymerization and Aggregation.

Laying the groundwork on preliminary structure-activity relationship study relating to the disruptive activity of cytochalasan derivatives on mammalian cell actin cytoskeleton, we furthered our study on the cytochalasans of the Dothideomycetes fungus, . A new cytochalasan analog triseptatin (), along with the previously described cytochalasans deoxaphomin B () and cytochalasin B (), and polyketide derivatives -4-hydroxy-6-deoxyscytalone () and 6-hydroxymellein () were isolated from the rice culture of . The structure of was elucidated through NMR spectroscopic analysis and high-resolution mass spectrometry (HR-ESI-MS).

Development of Predictive Classification Models for Whole Cell Antimycobacterial Activity of Benzothiazinones.

Nitrobenzothiazinones (BTZs) are a very potent class of antibiotics against . However, relationships between their structural properties and whole cell activity remain poorly predictable. Herein, we present the synthesis and antimycobacterial evaluation of a diverse set of BTZs.

COX Inhibitory and Cytotoxic Naphthoketal-Bearing Polyketides from .

Axenic fermentation on solid rice of the saprobic fungus afforded two new highly oxidized naphthalenoid polyketide derivatives, sparticatechol A () and sparticolin H () along with sparticolin A (). The structures of and were elucidated on the basis of their NMR and HR-ESIMS spectroscopic data. Assignment of absolute configurations was performed using electronic circular dichroism (ECD) experiments and Time-Dependent Density Functional Theory (TDDFT) calculations.

Chromane Derivatives from Underground Parts of and Their In Vitro Antimicrobial, Cytotoxicity and Antiproliferative Evaluation.

Phytochemical investigation of the ethanol extract of underground parts of Pall. afforded five new compounds; an unusual macrolide termed moniristenulide (), 5-methoxy-6,7-methylenedioxy-4--2'-cycloflavan (), 5,7,2',3'-tetrahydroxyflavanone (), 5-hydroxy-6,7-dimethoxyisoflavone-2'---d-glucopyranoside (), 5,2',3'-dihydroxy-6,7-dimethoxyisoflavone (), along with seven known compounds (-, -). The structures of all purified compounds were established by analysis of 1D and 2D NMR spectroscopy and HR-ESI-MS.

New Guaianolide Sesquiterpene Lactones and Other Constituents from Pyrethrum pulchrum.

is a rare Mongolian plant species that has been traditionally used as an ingredient in various remedies. Bioactivity-guided fractionation performed on the methanol extract of its aerial parts led to the isolation of 2 previously undescribed guaianolide-type sesquiterpene lactones, namely 1,10-epoxy-8-hydroxyguaia-3,11(13)-dien-6,12-olide (1: ) and 1,8,10-trihydroxyguaia-3,11(13)-dien-6,12-olide (2: ), along with the isolation or chromatographic identification of 11 compounds, arglabin (3: ), 3-hydroxycostunolide (4: ), isocostic acid (5: ), ()-9-(2-thienyl)-6-nonen-8-yn-3-ol (6: ), ()-9-(2-thienyl)-6-nonen-8-yn-3-ol (7: ), , , , -tetra-p-coumaroyl spermine (8: ), chlorogenic acid (9: ), 3,5-di--caffeoylquinic acid (10: ), 3,5-di--caffeoylquinic acid methyl ester (11: ), 3,4-di--caffeoylquinic acid (12: ), and tryptophan (13: ). Their structures were assigned based on spectroscopic and spectrometric data.

Total Synthesis and Bioactivity Mapping of Geodiamolide H.

The first total synthesis of the actin-stabilizing marine natural product geodiamolide H was achieved. Solid-phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring-closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F-actin target and property computation in silico, for a better understanding of structure-activity relationships (SAR).

Potential Cancer- and Alzheimer's Disease-Targeting Phosphodiesterase Inhibitors from : Insights from and Consensus Virtual Screening.

Inhibition of the major cyclic adenosine monophosphate-metabolizing enzyme PDE4 has shown potential for the discovery of drugs for cancer, inflammation, and neurodegenerative disorders such as Alzheimer's disease. As a springboard to explore new anti-cancer and anti-Alzheimer's chemical prototypes from rare Annonaceae species, the present study evaluated anti-PDE4B along with antiproliferative and anti-cholinesterase activities of the extracts of the Philippine endemic species using assays and framed the resulting biological significance through computational binding and reactivity-based experiments. Thus, the PDE4 B2B-inhibiting dichloromethane sub-extract (UaD) of elicited antiproliferative activity against chronic myelogenous leukemia (K-562) and cytostatic effects against human cervical cancer (HeLa).

Antibacterial and COX-2 Inhibitory Tetrahydrobisbenzylisoquinoline Alkaloids from the Philippine Medicinal Plant .

(Roxb. ex G.Don) J.

The impact of episporic modification of on virulence and interaction with phagocytes.

Fungal infections caused by the ancient lineage Mucorales are emerging and increasingly reported in humans. Comprehensive surveys on promising attributes from a multitude of possible virulence factors are limited and so far, focused on and . This study addresses a systematic approach to monitor phagocytosis after physical and enzymatic modification of the outer spore wall of , one of the major causative agents of mucormycosis.

Bioactive flavonoids from plant extract of and its acute toxicity.

Ledeb. has been a phytochemically unexplored Mongolian medicinal folklore plant. In this study, its total flavonoid content was determined and fourteen flavonoids () were isolated from the aerial parts of .

Functional surface proteomic profiling reveals the host heat-shock protein A8 as a mediator of Lichtheimia corymbifera recognition by murine alveolar macrophages.

Mucormycosis is an emergent, fatal fungal infection of humans and warm-blooded animals caused by species of the order Mucorales. Immune cells of the innate immune system serve as the first line of defence against inhaled spores. Alveolar macrophages were challenged with the mucoralean fungus Lichtheimia corymbifera and subjected to biotinylation and streptavidin enrichment procedures followed by LC-MS/MS analyses.

Quantitative Impact of Cell Membrane Fluorescence Labeling on Phagocytosis Measurements in Confrontation Assays.

Phagocytosis is series of steps where the pathogens and the immune cells interact during an invasion. This starts with the adhesion process between the host and pathogen cells, and is followed by the engulfment of the pathogens. Many analytical methods that are applied to characterize phagocytosis based on imaging the host-pathogen confrontation assays rely on the fluorescence labeling of cells.

Antitubercular and cytotoxic polyoxygenated cyclohexane derivatives from .

Chromatographic purification of the DCM sub-extract of led to the isolation and characterization of a new polyoxygenated cyclohexane derivative, grandifloranol (), together with five known compounds. Among the compounds isolated, zeylenone () showed moderate antitubercular activity against HRv with MIC value of 51.2 μM and antiproliferative or cytotoxic activity against human myeloid leukaemia (K-562) and HeLa cells with IC values of 2.

Mining Symbionts of a Spider-Transmitted Fungus Illuminates Uncharted Biosynthetic Pathways to Cytotoxic Benzolactones.

A spider-transmitted fungus (Rhizopus microsporus) that was isolated from necrotic human tissue was found to harbor endofungal bacteria (Burkholderia sp.). Metabolic profiling of the symbionts revealed a complex of cytotoxic agents (necroximes).

Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human- and Animal-Pathogenic Burkholderia Species.

Burkholderia species such as B. mallei and B. pseudomallei are bacterial pathogens causing fatal infections in humans and animals (glanders and melioidosis), yet knowledge on their virulence factors is limited.

The geographical region of origin determines the phagocytic vulnerability of Lichtheimia strains.

Mucormycoses are life-threatening infections that affect patients suffering from immune deficiencies. We performed phagocytosis assays confronting various strains of Lichtheimia species with alveolar macrophages, which form the first line of defence of the innate immune system. To investigate 17 strains from four different continents in a comparative fashion, transmitted light and confocal fluorescence microscopy was applied in combination with automated image analysis.

Bioactivity and Mode of Action of Bacterial Tetramic Acids.

Microbially produced 3-acyltetramic acids display a diverse range of biological activities. The pyreudiones are new members of this class that were isolated from bacteria of the genus . Here, we performed a structure-activity relationship study and determined their mode of action.

Author Correction: Arylmethylamino steroids as antiparasitic agents.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Biosynthesis of Diverse Antimicrobial and Antiproliferative Acyloins in Anaerobic Bacteria.

Metabolic profiling and genome mining revealed that anaerobic bacteria have the potential to produce acyloin natural products. In addition to sattazolin A and B, three new sattazolin congeners and a novel acyloin named clostrocyloin were isolated from three strains of , a bacterium used for industrial solvent production. Bioactivity profiling showed that the sattazolin derivatives possess antimicrobial activities against mycobacteria and pseudomonads with only low cytotoxicity.