7--Carboxylic Acid-Substituted 3--Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump.

Previously, we reported that 3--alkyl difluoroquercetins (di-F-Q) potentiates the antimicrobial activity of aztreonam (ATM) against metallo-β-lactamase (MBL)-producing through simultaneous inhibition of MBLs and efflux pumps. However, the ATM-potentiating activity of the 3--alkyl di-F-Q was observed only at high and potentially toxic concentrations (32 mg/L). As both MBLs and efflux pumps reside in the periplasm of Gram-negative bacteria, their inhibitors should accumulate in the periplasmic space.

Glycoside-metabolizing oxidoreductase D3dgpA from human gut bacterium.

The Gfo/Idh/MocA family enzyme DgpA was known to catalyze the regiospecific oxidation of puerarin to 3"-oxo-puerarin in the presence of 3-oxo-glucose. Here, we discovered that D3dgpA, cloned from the human gut bacterium sp. MRG-IFC3, catalyzed the regiospecific oxidation of various -/-glycosides, including puerarin, in the presence of methyl β-D-3-oxo-glucopyranoside.

3--Substituted Quercetin: an Antibiotic-Potentiating Agent against Multidrug-Resistant Gram-Negative Enterobacteriaceae through Simultaneous Inhibition of Efflux Pump and Broad-Spectrum Carbapenemases.

The discovery of safe and efficient inhibitors against efflux pumps as well as metallo-β-lactamases (MBL) is one of the main challenges in the development of multidrug-resistant (MDR) reversal agents which can be utilized in the treatment of carbapenem-resistant Gram-negative bacteria. In this study, we have identified that introduction of an ethylene-linked sterically demanding group at the 3-OH position of the previously reported MDR reversal agent di-F-Q endows the resulting compounds with hereto unknown multitarget inhibitory activity against both efflux pumps and broad-spectrum β-lactamases including difficult-to-inhibit MBLs. A molecular docking study of the multitarget inhibitors against efflux pump, as well as various classes of β-lactamases, revealed that the 3--alkyl substituents occupy the novel binding sites in efflux pumps as well as carbapenemases.

Potentiation of Antibiotic Activity of Aztreonam against Metallo-β-Lactamase-Producing Multidrug-Resistant by 3--Substituted Difluoroquercetin Derivatives.

The combination of aztreonam (ATM) and ceftazidime-avibactam (CAZ-AVI; CZA) has shown therapeutic potential against serine-β-lactamase (SBL)- and metallo-β-lactamase (MBL)-producing . However, the ability of CZA to restore the antibiotic activity of ATM is severely limited in MBL-producing multidrug-resistant (MDR) strains because of the myriad of intrinsic and acquired resistance mechanisms associated with this pathogen. We reasoned that the simultaneous inhibition of multiple targets associated with multidrug resistance mechanisms may potentiate the antibiotic activity of ATM against MBL-producing .

Production of Four Flavonoid -Glucosides in .

Flavonoid -glucosides, which are found in several plant families, are characterized by several biological properties, including antioxidant, anticancer, anti-inflammatory, neuroprotective, hepatoprotective, cardioprotective, antibacterial, antihyperalgesic, antiviral, and antinociceptive activities. The biosynthetic pathway of flavonoid -glucosides in plants has been elucidated. In the present study, a pathway was introduced to to synthesize four flavonoid -glucosides, namely, isovitexin, vitexin, kaempferol 6--glucoside, and kaempferol 8--glucoside.

Protection of Skin Fibroblasts from Infrared-A-Induced Photo-Damage Using Ginsenoside Rg3(S)-Incorporated Soybean Lecithin Liposomes.

Protection of skin cells from chronic infrared-A (IRA) irradiation is crucial for anti-photoaging of the skin. In this study, we investigated the protective activity of Rg3(S) and Rg3(S)-incorporated anionic soybean lecithin liposomes (Rg3/Lipo) with a size of approximately 150 nm against IRA-induced photodamage in human fibroblasts. The formulated Rg3/Lipo showed increased solubility in aqueous solution up to a concentration of 200 μg/ml, compared to free Rg3(S).

Phenolic C-glycoside synthesis using microbial systems.

Plants produce different types of phenolic compounds. The majority of these compounds are glycosylated. Phenolic O-glycosides are also common.

Exosome-mediated delivery of transforming growth factor-β receptor 1 kinase inhibitors and toll-like receptor 7/8 agonists for combination therapy of tumors.

In this study, combination therapy with the transforming growth factor-β receptor I (TGFβRI) kinase inhibitor SD-208 and a toll-like receptor (TLR)-7/8 agonist resiquimod (R848) was examined along with serum-derived exosomes (EXOs) as versatile carriers. SD-208-encapsulated EXOs (SD-208/EXOs) and R848-encapsulated EXOs (R848/EXOs) were successfully prepared with a size of 87 ± 8 nm and 51 ± 4 nm, respectively, which were stable in aqueous solution at pH 7.4.

Role of ginseng in the neurovascular unit of neuroinflammatory diseases focused on the blood-brain barrier.

Ginseng has long been considered as an herbal medicine. Recent data suggest that ginseng has anti-inflammatory properties and can improve learning- and memory-related function in the central nervous system (CNS) following the development of CNS neuroinflammatory diseases such as Alzheimer's disease, cerebral ischemia, and other neurological disorders. In this review, we discuss the role of ginseng in the neurovascular unit, which is composed of endothelial cells surrounded by astrocytes, pericytes, microglia, neural stem cells, oligodendrocytes, and neurons, especially their blood-brain barrier maintenance, anti-inflammatory effects and regenerative functions.

Synthesis of chlorogenic acid and p-coumaroyl shikimate by expressing shikimate gene modules in Escherichia coli.

Aim: Chlorogenic acid and p-coumaroyl shikimate are hydroxycinnamic acid derivatives. These compounds are nutraceutical supplements due to their biological activities including prevention of cardiovascular disease and cancers. These two compounds were synthesized in Escherichia coli through two-culture system using two mutants, which are biochemically interdependent.

Synthesis of 4-Hydroxybenzoic Acid Derivatives in .

Hydroxybenzoic acids (HBAs) such as 4-hydroxybenzoic acid (4-HBA) and 3,4-dihydroxybenzoic acid (DHB; protocatechuic acid) and its ester with methanol (methylparaben [MP]) are known to have various functional biological properties, including antibacterial, anticancer, antidiabetic, antiaging, antiviral, and anti-inflammatory activities. Since these compounds are widely used in cosmetic, food, and pharmaceutical industries, the use of renewable feedstocks for the production of HBAs is an area of growing interest. In this study, we used to synthesize these three hydroxybenzoic acid derivatives (4-HBA, DHB, and MP).

Synthesis of acridone derivatives via heterologous expression of a plant type III polyketide synthase in Escherichia coli.

Background: Acridone alkaloids are heterocyclic compounds that exhibit a broad-range of pharmaceutical and chemotherapeutic activities, including anticancer, antiviral, anti-inflammatory, antimalarial, and antimicrobial effects. Certain plant species such as Citrus microcarpa, Ruta graveolens, and Toddaliopsis bremekampii synthesize acridone alkaloids from anthranilate and malonyl-CoA.

Results: We synthesized two acridones in Escherichia coli.

Biosynthesis of Two Hydroxybenzoic Acid-Amine Conjugates in Engineered .

Two hydroxybenzoyl amines, 4-hydroxybenzoyl tyramine (4-HBT) and -2-hydroxybenzoyl tryptamine (2-HBT), were synthesized using . While 4-HBT was reported to demonstrate anti-atherosclerotic activity, 2-HBT showed anticonvulsant and antinociceptive activities. We introduced genes chorismate pyruvate-lyase (), tyrosine decarboxylase (), isochorismate synthase (), isochorismate pyruvate lyase (), and tryptophan decarboxylase () for each substrate, 4-hydroxybenzoic acid (4-HBA), tyramine, 2-hydroxybenzoic acid (2-HBA), and tryptamine, respectively, in .

Synthesis of Three Bioactive Aromatic Compounds by Introducing Polyketide Synthase Genes into Engineered .

Intermediates in aromatic amino acid biosynthesis can serve as substrates for the synthesis of bioactive compounds. In this study we used two intermediates in the shikimate pathway of , chorismate and anthranilate, to synthesize three bioactive compounds: 4-hydroxycoumarin (4-HC), 2,4-dihydroxyquinoline (DHQ), and 4-hydroxy-1-methyl-2(1H)-quinolone (NMQ). We introduced genes for the synthesis of salicylic acid from chorismate to supply the substrate for 4-HC and the gene encoding -methyltransferase for the synthesis of -methylanthranilate from anthranilate.

Synthesis of Methylated Anthranilate Derivatives Using Engineered Strains of .

Anthranilate derivatives have been used as flavoring and fragrant agents for a long time. Recently, these compounds are gaining attention due to new biological functions including antinociceptive and analgesic activities. Three anthranilate derivatives, -methylanthranilate, methyl anthranilate, and methyl -methylanthranilate were synthesized using metabolically engineered stains of .

Synthesis of Diverse Hydroxycinnamoyl Phenylethanoid Esters Using Escherichia coli.

Caffeic acid phenethyl ester (CAPE) is an ester of a hydroxycinnamic acid (phenylpropanoid) and a phenylethanoid (2-phenylethanol; 2-PE), which has long been used in traditional medicine. Here, we synthesized 54 hydroxycinnamic acid-phenylethanoid esters by feeding 64 combinations of hydroxycinnamic acids and phenylethanols to Escherichia coli harboring the rice genes OsPMT and Os4CL. The same approach was applied for ester synthesis with caffeic acid and eight different phenyl alcohols.

Stepwise Synthesis of Quercetin Bisglycosides Using Engineered .

Synthesis of flavonoid glycoside is difficult due to diverse hydroxy groups in flavonoids and sugars. As such, enzymatic synthesis or biotransformation is an approach to solve this problem. In this report, we used stepwise biotransformation to synthesize two quercetin bisglycosides (quercetin 3--glucuronic acid 7--rhamnoside [Q-GR] and quercetin 3--arabinose-7--rhamnoside [Q-AR]) because quercetin -rhamnosides contain antiviral activity.

Current Status of Microbial Phenylethanoid Biosynthesis.

Phenylethanoids, including 2-phenylethanol, tyrosol, and salidroside are a group of phenolic compounds with a C6-C2 carbon skeleton synthesized by plants. Phenylethanoids display a variety of biological activities, including antibacterial, anticancer, anti-inflammatory, neuroprotective, and anti-asthmatic activities. Recently, successful microbial synthesis of phenylethanoids through metabolic engineering and synthetic biology approaches has been reported and could allow phenylethanoid production from alternative microbial sources.

Synthesis of avenanthramides using engineered Escherichia coli.

Background: Hydroxycinnamoyl anthranilates, also known as avenanthramides (avns), are a group of phenolic alkaloids with anti-inflammatory, antioxidant, anti-itch, anti-irritant, and antiatherogenic activities. Some avenanthramides (avn A-H and avn K) are conjugates of hydroxycinnamic acids (HC), including p-coumaric acid, caffeic acid, and ferulic acid, and anthranilate derivatives, including anthranilate, 4-hydroxyanthranilate, and 5-hydroxyanthranilate. Avns are primarily found in oat grain, in which they were originally designated as phytoalexins.

Engineering of Escherichia coli for the synthesis of N-hydroxycinnamoyl tryptamine and serotonin.

Plants synthesize various phenol amides. Among them, hydroxycinnamoyl (HC) tryptamines and serotonins exhibit antioxidant, anti-inflammatory, and anti-atherogenic activities. We synthesized HC-tryptamines and HC-serotonin from several HCs and either tryptamine or serotonin using Escherichia coli harboring the 4CL (4-coumaroyl CoA ligase) and CaHCTT [hydroxycinnamoyl-coenzyme A:serotonin N-(hydroxycinnamoyl)transferase] genes.

Production of three phenylethanoids, tyrosol, hydroxytyrosol, and salidroside, using plant genes expressing in Escherichia coli.

Polyphenols, which include phenolic acids, flavonoids, stilbenes, and phenylethanoids, are generally known as useful antioxidants. Tyrosol, hydroxytyrosol, and salidroside are typical phenylethanoids. Phenylethanoids are found in plants such as olive, green tea, and Rhodiola and have various biological activities, including the prevention of cardiovascular diseases, cancer, and brain damage.

Production of Curcuminoids in .

Curcumin, a hydrophobic polyphenol derived from the rhizome of the herb , possesses diverse pharmacological properties, including anti-inflammatory, antioxidant, antiproliferative, and antiangiogenic activities. Two curcuminoids (dicinnamoylmethane and bisdemethoxycurcumin) were synthesized from glucose in . (phenylalanine ammonia lyase) or (tyrosine ammonia lyase), along with (-coumaroyl-CoA ligase) and (curcumin synthase) genes, were introduced into , and each strain produced dicinnamoylmethane or bisdemethoxycurcumin, respectively.

Biosynthesis of three N-acetylaminosugar-conjugated flavonoids using engineered Escherichia coli.

Background: Nucleotide sugars serve as sugar donors for the synthesis of various glycones. The biological and chemical properties of glycones can be altered depending which sugar is attached. Bacteria synthesize unusual nucleotide sugars.

Biological Synthesis of Baicalein Derivatives Using .

Two baicalein derivatives, baicalin and oroxylin A, were synthesized in this study. These derivatives exhibit diverse biological activities, such as anxiolytic and anticancer activities as well as memory enhancement. In order to synthesize baicalin from aglycon baicalein using , we utilized a glycosyltransferase that regioselectively transfers glucuronic acid from UDP-glucuronic acid to the 7-hydroxy group of baicalein.