Rejuvenation of Meropenem by Conjugation with Tilapia Piscidin-4 Peptide Targeting NDM-1 .

Gram-negative pathogens that produce β-lactamases pose a serious public health threat as they can render β-lactam antibiotics inactive via hydrolysis. This action contributes to the waning effectiveness of clinical antibiotics and creates an urgent need for new antimicrobials. Antimicrobial peptides (AMPs) exhibiting multimodal functions serve as a potential source in spite of a few limitations.

Potential natural product 3,4-seco-schitriterpenoids from Kadsura japonica L. as anti-neuroinflammatory agents.

In the present study, the undescribed schitriterpenoids, kadsujanonols A-I (1-9), and eleven reported compounds (10-20) were isolated from K. japonica L. vines.

Anti-inflammatory effect of euphane- and tirucallane-type triterpenes isolated from the traditional herb L.

The Euphorbiaceae plant L. is distributed widely in India, Thailand, Southeastern China, and Taiwan and used as a carminative and expectorant to treat several inflammation-related diseases, such as gonorrhoea, asthma, and cancer. In the course of our search for potential anti-inflammatory agents from the titled plant, 11 triterpenes from the stem of were isolated and reported in our previous endeavor.

N-Formimidoylation/-iminoacetylation modification in aminoglycosides requires FAD-dependent and ligand-protein NOS bridge dual chemistry.

Oxidized cysteine residues are highly reactive and can form functional covalent conjugates, of which the allosteric redox switch formed by the lysine-cysteine NOS bridge is an example. Here, we report a noncanonical FAD-dependent enzyme Orf1 that adds a glycine-derived N-formimidoyl group to glycinothricin to form the antibiotic BD-12. X-ray crystallography was used to investigate this complex enzymatic process, which showed Orf1 has two substrate-binding sites that sit 13.

β-Hydroxylation of α-amino-β-hydroxylbutanoyl-glycyluridine catalyzed by a nonheme hydroxylase ensures the maturation of caprazamycin.

Caprazamycin is a nucleoside antibiotic that inhibits phospho-N-acetylmuramyl-pentapeptide translocase (MraY). The biosynthesis of nucleoside antibiotics has been studied but is still far from completion. The present study characterized enzymes Cpz10, Cpz15, Cpz27, Mur17, Mur23 out of caprazamycin/muraymycin biosynthetic gene cluster, particularly the nonheme αKG-dependent enzyme Cpz10.

Kaguacidine A: a novel spirohydantoin-containing cucurbitane glycoside from vines of L.

The spirohydantoin-containing cucurbitane-type triterpenoid, kaguacidine A (), was isolated and purified from 95% ethanol extract of vines of L. (Cucurbitaceae). Its unprecedented chemical structure, a spirohydantoin substituent at C-23 of cucurbitane, was elucidated by extensive spectroscopic analyses, including HRESIMS, IR, optical rotation, 1 D- and 2 D-NMR spectra.

Novel Aporphine- and Proaporphine-Clerodane Hybrids Identified from the Barks of Taiwanese (Sonn.) Thwaites var. with Strong Anti-DENV2 Activity.

Hybrid natural products produced via mixed biosynthetic pathways are unique and often surprise one with unexpected medicinal properties in addition to their fascinating structural complexity/diversity. In view of chemical structures, hybridization is a way of diversifying natural products usually through dimerization of two similar or dissimilar subcomponents through a C-C or N-C covalent linkage. Here, we report four structurally attractive diterpene-alkaloid conjugates polyalongarins A-D (-), clerodane-containing aporphine and proaporphine alkaloids, the first of its kind from the barks of Taiwanese (Sonn.

Anti-inflammatory sesquiterpene and triterpene acids from Hemsley.

Hemsley is a plant conventionally processed to provide popular food materials and herbal medicines in Asia. In this study, six triterpene acids, including five new ones (mesonaic acids D-H, -), and one proximadiol-type sesquiterpene () were isolated from the methanolic extract of the air-dried . Chemical structures of ‒ were established by spectroscopic methods, especially 2D NMR techniques (H-H COSY, HSQC, HMBC, and NOESY) and HRESIMS.

Intermolecular Interactions of Nucleoside Antibiotic Tunicamycin with On-Target MraY-TUN and Off-Target DPAGT1-TUN in the Active Sites Delineated by Quantum Mechanics/Molecular Mechanics Calculations.

Tunicamycin (TUN) is a nucleoside antibiotic with a complex structure comprising uracil, tunicamine sugar, -acetylglucosamine (GlcNAc), and fatty acyl tail moieties. TUN, known as a canonical inhibitor, blocks vital functions of certain transmembrane protein families, for example, the insect enzyme dolichyl phosphate α--acetylglucosaminylphosphotransferase (DPAGT1) of and the bacterial enzyme phospho--acetylmuramoylpentapeptide translocase (MraY) of . Accurate description of protein-drug interactions has an immense impact on structure-based drug design, while the main challenge is to create proper topology and parameter entries for TUN in modeling protein-TUN interactions given the structural complexity.

Genetic and Biochemical Characterization of Halogenation and Drug Transportation Genes Encoded in the Albofungin Biosynthetic Gene Cluster.

Albofungin, a hexacyclic aromatic natural product, exhibits broad-spectrum antimicrobial activity. Its biosynthesis, regulation, and resistance remain elusive. Here, we report the albofungin () biosynthetic gene cluster (BGC) from its producing strain Streptomyces tumemacerans JCM5050.

Four cucurbitane glycosides taimordisins A-D with novel furopyranone skeletons isolated from the fruits of .

Four novel triterpene glycosides, taimordisins A-D (-), were discovered from fresh fruits of Taiwanese . The chemical framework and relative stereochemistry of these four natural products were isolated, purified, and determined by using various separation and spectroscopy techniques. Each of them features a unique bicyclic-fused or trifuso-centro-fused ring system.

KasQ an Epimerase Primes the Biosynthesis of Aminoglycoside Antibiotic Kasugamycin and KasF/H Acetyltransferases Inactivate Its Activity.

Kasugamycin (KSM), an aminoglycoside antibiotic, is composed of three chemical moieties: D--inositol, kasugamine and glycine imine. Despite being discovered more than 50 years ago, the biosynthetic pathway of KSM remains an unresolved puzzle. Here we report a structural and functional analysis for an epimerase, KasQ, that primes KSM biosynthesis rather than the previously proposed KasF/H, which instead acts as an acetyltransferase, inactivating KSM.

Fucoidan from Sargassum hemiphyllum inhibits infection and inflammation of Helicobacter pylori.

Having infected by Helicobacter pylori, the infection often leads to gastritis, gastric ulcer, or even gastric cancer. The disease is typically treated with antibiotics as they used to effectively inhibit or kill H. pylori, thus reducing the incidence of gastric adenoma and cancer to significant extent.

Dual-Mechanism Confers Self-Resistance to the Antituberculosis Antibiotic Capreomycin.

Capreomycin (CMN) is an important second-line antituberculosis antibiotic isolated from subspecies . The gene cluster for CMN biosynthesis has been identified and sequenced, wherein the gene was annotated as a phosphotransferase likely engaging in self-resistance. Previous studies reported that Cph inactivates two CMNs, CMN IA and IIA, by phosphorylation.

Topical application of fucoidan derived from Cladosiphon okamuranus alleviates atopic dermatitis symptoms through immunomodulation.

Atopic dermatitis (AD) is a T helper (Th) 2 cell-mediated allergic disease, which features increased number of immunocytes and level of Th2-associated cytokines. Fucoidan is well known a naturally occurring agent effectively ameliorating many AD symptoms. Though these alleviative effects are exhilarating, the mechanisms behind, however, are still rather limited.

Immunomodulation and mechanisms of fucoidan from Cladosiphon okamuranus ameliorates atopic dermatitis symptoms.

Atopic dermatitis (AD) is a long-term allergic skin disorder that occurs most frequently in children. Currently, the common treatment of AD is corticosteroids; however, the drugs cause serious side effects. Therefore, there are many patients who seek complementary and alternative treatments such as healthy food.

Labeling and Characterization of Phenol-Containing Glycopeptides Using Chemoselective Probes with Isotope Tags.

Secondary metabolites are structurally diverse natural products (NPs) and have been widely used for medical applications. Developing new tools to enrich NPs can be a promising solution to isolate novel NPs from the native and complex samples. Here, we developed native and deuterated chemoselective labeling probes to target phenol-containing glycopeptides by the ene-type labeling used in proteomic research.

Theoretical Study of Intermolecular Interactions between Critical Residues of Membrane Protein MraY and Promising Antibiotic Muraymycin D2.

Phospho--acetylmuramoyl-pentapeptide translocase (MraY) from is the binding target for the nucleotide antibiotic muraymycin D2 (MD2). MraY in the presence of the MD2 ligand has been crystallized and released, while the interactions between the ligand and active-site residues remain less quantitatively and qualitatively defined. We characterized theoretically the key residues involved in noncovalent interactions with MD2 in the MraY active site.

Positive Effects of Preventive Nutrition Supplement on Anticancer Radiotherapy in Lung Cancer Bearing Mice.

(1) : Radiotherapy (RT) is one of the major treatments for non-small cell lung cancer, but RT-associated toxicities usually impede its anticancer effect. Nutrient supplementation has been applied for cancer prevention or a complementary measure to anticancer therapy. Here, we explored the influence of total nutrition supplementation before and after cancer occurrence on the anticancer benefit and side effects of RT.

Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase.

Plant type III polyketide synthases produce diverse bioactive molecules with a great medicinal significance to human diseases. Here, we demonstrated versatility of a stilbene synthase (STS) from , which can accept various non-physiological substrates to form unnatural polyketide products. Three enzymes (4-coumarate CoA ligase, malonyl-CoA synthetase and engineered benzoate CoA ligase) along with synthetic chemistry was practiced to synthesize starter and extender substrates for STS.

Structural and chemical trapping of flavin-oxide intermediates reveals substrate-directed reaction multiplicity.

Though reactive flavin-N5/C4α-oxide intermediates can be spectroscopically profiled for some flavin-assisted enzymatic reactions, their exact chemical configurations are hardly visualized. Structural systems biology and stable isotopic labelling techniques were exploited to correct this stereotypical view. Three transition-like complexes, the α-ketoacid…N5-FMN complex (I), the FMN -N5-aloxyl-C'α -C4α zwitterion (II), and the FMN-N5-ethenol-N5-C4α-epoxide (III), were determined from mandelate oxidase (Hmo) or its mutant Y128F (monooxygenase) crystals soaked with monofluoropyruvate (a product mimic), establishing that N5 of FMN an alternative reaction center can polarize to an ylide-like mesomer in the active site.

The Combination of and Inhibits Lung Cancer and Cachexia through Its Immunomodulatory Function.

Lung cancer and its related cachexia are the leading cause of cancer death in the world. In this study, we report the inhibitory effect of the combined therapy of and , on tumor growth and cachexia in tumor-bearing mice. Lewis lung carcinoma cells were inoculated into male C57BL/6 and CAnN.

The flavin mononucleotide cofactor in α-hydroxyacid oxidases exerts its electrophilic/nucleophilic duality in control of the substrate-oxidation level.

The Y128F single mutant of p-hydroxymandelate oxidase (Hmo) is capable of oxidizing mandelate to benzoate via a four-electron oxidative decarboxylation reaction. When benzoylformate (the product of the first two-electron oxidation) and hydrogen peroxide (an oxidant) were used as substrates the reaction did not proceed, suggesting that free hydrogen peroxide is not the committed oxidant in the second two-electron oxidation. How the flavin mononucleotide (FMN)-dependent four-electron oxidation reaction takes place remains elusive.

Antitumor, Inhibition of Metastasis and Radiosensitizing Effects of Total Nutrition Formula on Lewis Tumor-Bearing Mice.

Non-small-cell lung cancer (NSCLC) causes high mortality. Radiotherapy is an induction regimen generally applied to patients with NSCLC. In view of therapeutic efficacy, the outcome is not appealing in addition to bringing about unwanted side effects.

Biochemical and structural explorations of α-hydroxyacid oxidases reveal a four-electron oxidative decarboxylation reaction.

p-Hydroxymandelate oxidase (Hmo) is a flavin mononucleotide (FMN)-dependent enzyme that oxidizes mandelate to benzoylformate. How the FMN-dependent oxidation is executed by Hmo remains unclear at the molecular level. A continuum of snapshots from crystal structures of Hmo and its mutants in complex with physiological/nonphysiological substrates, products and inhibitors provides a rationale for its substrate enantioselectivity/promiscuity, its active-site geometry/reactivity and its direct hydride-transfer mechanism.