Identification of a l-Threonine-Utilizing Hydrazine Synthetase for Thrazarine Biosynthesis in Streptomyces coerulescens MH802-fF5.

Hydrazine synthetases (HSs), consisting of cupin and methionyl-tRNA synthetase (MetRS)-like domains, catalyze hydrazine formation in the biosynthesis of various nitrogennitrogen (NN) bond-containing secondary metabolites. The structural diversity of the NN bond-containing secondary metabolites synthesized using this system is attributed to the diversity of amino acids (e.g.

Study about fluostatins: efficient preparation of fluostatin A and discovery of fluostatin derivatives from Streptomyces sp. TA-3391.

Fluostatins are a class of compounds having four unique ring systems. They were originally isolated as dipeptidyl peptidase III (DPP3) inhibitors, and various derivatives and activities have been reported. In this study, fluostatin A, which is difficult to prepare by fermentative production, was effectively prepared by the transformation of fluostatin B.

New oligomycin derivatives inhibit anchorage-independent growth of pancreatic cancer cells.

Cancer stem cells (CSCs) play a crucial role in cancer progression, recurrence, and therapy resistance through their abilities to self-renew, differentiate, and evade treatment. Disrupting the interaction between CSCs and their tumor microenvironment, especially cancer-associated fibroblasts (CAFs), represents a promising therapeutic strategy. We screened microbial metabolites to identify compounds that specifically inhibit anchorage-independent (3D) growth, a key characteristic of CSCs, in the presence of CAF-conditioned medium (CAF-CM).

Total Synthesis of Kanamycins.

Structurally modified aminoglycosides, such as kanamycin, have shown promise as antibiotics and premature termination codon read-through drugs to fight against drug-resistant bacteria and to treat genetic diseases, respectively. Therefore, research on developing and discovering aminoglycoside antibiotics has recently increased. However, synthetic strategies for controllably positioning the two 1,2-cis-glycoside moieties on the symmetrical structure of kanamycin have not yet been established.

Creation of a macrolide antibiotic against non-tuberculous using late-stage boron-mediated aglycon delivery.

Non-tuberculous mycobacteria (NTM) is gaining clinical recognition as a recently emerging pulmonary pathogen. complex (MAC), the most common NTM, is the cause of pulmonary MAC disease. Currently, the macrolide azithromycin (AZM) is the standard first-line antibiotic for treatment of the disease.

Novobiocin primarily targets ParE in Neisseria gonorrhoeae.

Multidrug-resistant Neisseria gonorrhoeae is a pathogenic bacterium that poses a public health concern. In this study, we aimed to elucidate the mode of action of the conventional antibiotic novobiocin, which has been selected as a leading compound for novel antigonococcal drugs. Unlike other previously studied bacteria strains, novobiocin-resistant N.

Thiazoplanomicin, a new thiazolyl peptide antibiotic from the leaf-litter actinomycete Actinoplanes sp. MM794L-181F6.

A new bioactive substance was identified from a leaf-litter actinomycete strain by screening for antibacterial activity against Neisseria gonorrhoeae. The thiazolyl peptide antibiotic, named thiazoplanomicin, was isolated from the secondary metabolites of the leaf-litter actinomycetes Actinoplanes sp. MM794L-181F6 by extraction with n-butanol, silica gel column chromatography, Sephadex LH-20 column chromatography, and preparative HPLC.

Synthesis and biochemical characterization of naphthoquinone derivatives targeting bacterial histidine kinases.

Waldiomycin is an inhibitor of histidine kinases (HKs). Although most HK inhibitors target the ATP-binding region, waldiomycin binds to the intracellular dimerization domain (DHp domain) with its naphthoquinone moiety presumed to interact with the conserved H-box region. To further develop inhibitors targeting the H-box, various 2-aminonaphthoquinones with cyclic, aliphatic, or aromatic amino groups and naphtho [2,3-d] isoxazole-4,9-diones were synthesized.

Analysis of the Valgamicin Biosynthetic Pathway Reveals a General Mechanism for Cyclopropanol Formation across Diverse Natural Product Scaffolds.

Cyclopropanol rings are highly reactive and may function as molecular "warheads" that affect natural product bioactivity. Yet, knowledge on their biosynthesis is limited. Using gene cluster analyses, isotope labeling, and in vitro enzyme assays, we shed first light on the biosynthesis of the cyclopropanol-substituted amino acid cleonine, a residue in the antimicrobial depsipeptide valgamicin C and the cytotoxic glycopeptide cleomycin A2.

Direct visualization of ribosomes in the cell-free system revealed the functional evolution of aminoglycoside.

The rapid emergence of multi-drug-resistant bacteria has raised a serious public health concern. Therefore, new antibiotic developments have been highly desired. Here, we propose a new method to visualize antibiotic actions on translating ribosomes in the cell-free system under macromolecular crowding conditions by cryo-electron microscopy, designated as the DARC method: the Direct visualization of Antibiotic binding on Ribosomes in the Cell-free translation system.

Catenulopyrizomicins, new anti-Hepatitis B virus compounds, from the rare actinomycete Catenuloplanes sp. MM782L-181F7.

Hepatitis B virus (HBV) causes chronic hepatitis in humans, and current antiviral therapies rarely treat viral infections. To improve the treatment efficacy, novel therapeutic agents, especially those with different mechanisms of action, need to be developed for use in combination with the current antivirals. Here, we isolated new anti-HBV compounds, named catenulopyrizomicins A-C, from the fermentation broth of rare actinomycete Catenuloplanes sp.

Two new adenopeptins B and C inhibit sphere formation of pancreatic cancer cells.

Cancer remains one of the leading causes of death worldwide, particularly pancreatic cancer being lethal because of its aggressiveness and lack of early detection methods. A factor that contributes to malignancy are cancer stem cell-like characteristics promoted by the tumor-stromal interaction. Given that fibroblast conditioned medium (CM) promotes sphere formation of cancer cells, a cancer stem cell-like characteristic, its inhibitor could be a new anticancer agent.

Cycloimidamicins, Novel natural lead compounds for translation inhibition in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the most concerning pathogenic bacteria. We screened antibiotics using a highly drug-sensitive P. aeruginosa strain and an oligotrophic medium, and successfully isolated novel antibiotics, namely cycloimidamicins (CIMs), from a rare actinomycete strain, Lentzea sp.

Synthesis of novobiocin derivatives and evaluation of their antigonococcal activity and pharmacokinetics.

Gonorrhea has become a serious problem because the number of infected people is increasing and the multi-drug resistance of the causative bacteria, Neisseria gonorrhoeae, is progressing. To develop novel drugs against resistant N. gonorrhoeae, we focused on the antibiotic novobiocin (1).

Concise Total Synthesis and Biological Evaluation of Pargamicin A and its Diastereomer, Piperazic Acid-containing Cyclopeptides.

We have accomplished the total synthesis, structure determination, and biological evaluation of pargamicin A and one of its diastereomers. Two key tripeptide segments were synthesized using a linear peptide elongation process that includes the direct coupling of a poorly nucleophilic piperazic acid derivative. The resulting tripeptides were coupled using triphosgene/collidine at ambient temperature leading to a precursor for the final cyclization step.

Antiplasmodial Activity Evaluation of a Bestatin-Related Aminopeptidase Inhibitor, Phebestin.

The increasing burden and spread of resistant malaria parasites remains an immense burden to public health. These factors have driven the demand to search for a new therapeutic agent. From our screening, phebestin stood out with nanomolar efficacy against Plasmodium falciparum 3D7.

Aprosamine Derivatives Active against Multidrug-Resistant Gram-Negative Bacteria.

Novel aprosamine derivatives were synthesized for the development of aminoglycoside antibiotics active against multidrug-resistant Gram-negative bacteria. The synthesis of aprosamine derivatives involved glycosylation at the C-8' position and subsequent modification (epimerization and deoxygenation at the C-5 position and 1--acylation) of the 2-deoxystreptamine moiety. All 8'-β-glycosylated aprosamine derivatives (-) showed excellent antibacterial activity against carbapenem-resistant and 16S ribosomal RNA methyltransferase-producing multidrug-resistant Gram-negative bacteria compared to the clinical drug, arbekacin.

An efficient CRISPR interference-based prediction method for synergistic/additive effects of novel combinations of anti-tuberculosis drugs.

Tuberculosis (TB) is treated by chemotherapy with multiple anti-TB drugs for a long period, spanning 6 months even in a standard course. In perspective, to prevent the emergence of antimicrobial resistance, novel drugs that act synergistically or additively in combination with major anti-TB drugs and, if possible, shorten the duration of TB therapy are needed. However, their combinatorial effect cannot be predicted until the lead identification phase of the drug development.

Wychimicins, a new class of spirotetronate polyketides from Actinocrispum wychmicini MI503-A4.

In the course of our screening program for new anti-methicillin-resistant Staphylococcus aureus antibiotics, four novel antibiotics, termed wychimicins A-D, were isolated from the culture broth of the rare actinomycete Actinocrispum wychmicini strain MI503-AF4. Wychimicins are spirotetronates possessing a macrocyclic 13-membered ring containing trans-decalin and β-D-xylo-hexopyranose moieties connected to C-17 by an O-glycosidic linkage according to MS, NMR and X-ray analyses. In X-ray crystal structure analysis, the Flack constant was 0.

Synthesis of Mannosylerythritol Lipid Analogues and their Self-Assembling Properties, Recovery Effects on Damaged Skin Cells, and Antibacterial Activity.

Synthesis of three types of purpose-designed mannosylerythritol lipid (MEL)-D analogues with decanoyl groups, β-GlcEL-D, α-GlcEL-D, and α-MEL-D, was accomplished utilizing our boron-mediated aglycon delivery (BMAD) methods. Their self-assembling properties, recovery effects on damaged skin cells, and antibacterial activity were evaluated. It was revealed, for the first time, that α-GlcEL-D and α-MEL-D only generated giant vesicles, indicating that slight differences in the steric configuration of an erythritol moiety and fatty acyl chains affect the ability to form vesicles.

Rediscovery of 4-Trehalosamine as a Biologically Stable, Mass-Producible, and Chemically Modifiable Trehalose Analog.

Nonreducing disaccharide trehalose is used as a stabilizer and humectant in various products and is a potential medicinal drug, showing curative effects on the animal models of various diseases. However, its use is limited as it is hydrolyzed by trehalase, a widely expressed enzyme in multiple organisms. Several trehalose analogs are prepared, including a microbial metabolite 4-trehalosamine, and their high biological stability is confirmed.