Potent Activity Research Articles

Phytochemical screening and in vitro antibacterial activity of Moringa oleifera (Lam.) leaf extract

The study aimed to investigate the phytochemical constituents and antibacterial activity of ethanolic extract of Moringa oleifera Lam. belonging to family Moringaceae. Moringa oleifera is an interesting plant for its use in bioactive compounds. Ethanol and Distilled water were used as a solvent to extract and to detect the phytochemical constituent’s and to screen its antibacterial activity from the leaves of Moringa oleifera. The phytochemical constituents were screened by qualitative analysis method. The phytochemical screening finds out the presence of terpenoids, phenols, tannins, flavonoids, glycosides, etc. in leaf extract of Moringa oleifera. The antibacterial activity of ethanolic leaf extract of Moringa oleifera was examined against gram positive bacteria (Staphylococcus aureus) and gram-negative bacteria (Escherichia coli). Antibacterial Activity were carried out with ethanolic extract of Moringa oleifera using agar well diffusion method. The present study showed that ethanolic extract of Moringa oleifera showed more potent antibacterial activity against S. Aureus and E. coli.

Gprc5a is a novel parathyroid hormone-inducible gene and negatively regulates osteoblast proliferation and differentiation.

Teriparatide is a peptide derived from a parathyroid hormone (PTH) and an osteoporosis therapeutic drug with potent bone formation-promoting activity. To identify novel druggable genes that act downstream of PTH signaling and are potentially involved in bone formation, we screened PTH target genes in mouse osteoblast-like MC3T3-E1 cells. Here we show that Gprc5a, encoding an orphan G protein-coupled receptor, is a novel PTH-inducible gene and negatively regulates osteoblast proliferation and differentiation. PTH treatment induced Gprc5a expression in MC3T3-E1 cells, rat osteosarcoma ROS17/2.8 cells, and mouse femurs. Induction of Gprc5a expression by PTH occurred in the absence of protein synthesis and was mediated primarily via the cAMP pathway, suggesting that Gprc5a is a direct target of PTH signaling. Interestingly, Gprc5a expression was induced additively by co-treatment with PTH and 1α, 25-dihydroxyvitamin D3 (calcitriol), or retinoic acid in MC3T3-E1 cells. Reporter analysis of a 1 kb fragment of human GPRC5A promoter revealed that the promoter fragment showed responsiveness to PTH via the cAMP response element, suggesting that GPRC5A is also a PTH-inducible gene in humans. Gprc5a knockdown promoted cell viability and proliferation, as demonstrated by MTT and BrdU assays. Gprc5a knockdown also promoted osteoblast differentiation, as indicated by gene expression analysis and mineralization assay. Mechanistic studies showed that Gprc5a interacted with BMPR1A and suppressed BMP signaling induced by BMP-2 and constitutively active BMP receptors, ALK2 (ACVR1) Q207D and ALK3 (BMPR1A) Q233D. Thus, our results suggest that Gprc5a is a novel gene induced by PTH that acts in an inhibitory manner on both cell proliferation and osteoblast differentiation and is a candidate for drug targets for osteoporosis.

Bioassay-guided isolation and identification of antibacterial compounds from Piper betle leaf with inhibitory activity against the Vibrio species in shrimp

Bioassay-guided isolation and identification of antibacterial compounds from <i>Piper betle</i> leaf with inhibitory activity against the <i>Vibrio</i> species in shrimp

Synergistic antibacterial effect of ginsenoside Rh2 and calcium hydroxide on Enterococcus faecalis.

Treatment of root canal infections becomes more challenging due to the extremely high tolerance of Enterococcus faecalis (E. faecalis) to calcium hydroxide (Ca(OH)2). Ginsenoside is a Chinese herbal extract that has been proven to have antimicrobial properties and synergistic activities. And this study evaluated the antibacterial activity of ginsenoside Rh2 in combination with Ca(OH)2 against E. faecalis and its preliminary mechanism of action. Broth microdilution method, checkerboard dilution method, time-inhibition curve, drug resistance assays, scanning electron microscopy, and biofilm inhibition and removal assays indicated that Rh2 in combination with Ca(OH)2 exhibited potent antibacterial activity against E. faecalis. Rh2 exerted significant in vitro antibacterial activity against E. faecalis, with a minimum inhibitory concentration (MIC) of 3.125μg/mL and minimum bactericidal concentration (MBC) of 6.25μg/mL, and significantly enhanced the susceptibility of E. faecalis to Ca(OH)2 (FICI = 0.5). Furthermore, cell membrane permeability assays, surface hydrophobicity assays, ATPase activity assays, and intra-biofilm extracellular polysaccharides (EPS) assays revealed that Rh2 and Ca(OH)2 synergistically inhibit bacteria mainly by increasing membrane permeability. Ultimately, cytotoxicity assays showed that Rh2 exhibited only low toxicity, the half maximal inhibitory concentration (IC50) of Rh2 was 19.75μg/mL. This study confirmed the synergistic antibacterial activities of Rh2 and Ca(OH)2 against E. faecalis. Our findings indicate that the Rh2 and Ca(OH)2 combination may be a promising alternative approach to treating root canal infections.

Hydrazine-1-Carboxamide Conjugated Silver Nanoprobe for Trace Level Detection of Hg2+ with Potent Antibacterial Activity

Hydrazine-1-Carboxamide Conjugated Silver Nanoprobe for Trace Level Detection of Hg2+ with Potent Antibacterial Activity

Novel biaryloxazolidinone derivatives with broad-spectrum antibacterial activity, favorable drug-like profiles and in vivo efficacy against linezolid-resistant Staphylococcusaureus

The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC=0.06μg/mL), MSSA (MIC=0.125μg/mL), MRSA (MIC=0.06μg/mL), LRSA (MIC=0.125μg/mL) and LREFa (MIC=0.5μg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49h, high peak plasma concentration (Cmax=2320ng/mL), high plasma exposure (AUC0-t=8310hng/mL), and superior oral bioavailability (F=68.1%) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection.

Synthesis, structure, and mechanism of action of a unique mixed-ligand nickel (II)-complex of tetra-dentate phenol-based ligand with di-aquo co-ligands with significant pro-apoptotic and anti-metastatic effect against malignant human cancer cells

From the discovery of the anticancer activity of “cisplatin”, various type of numerous mononuclear platinum (II) complexes has been evaluated for antitumor activities, though therapeutic use is limited due to side effects and resistance. In this study, A unique mixed ligand mono nuclear octahedral Ni (II) complex [NiL(H2O)2].0·.5H2O (1) [H2L = N,Nʹ-dimethyl-N,Nʹ-bis (2-hydroxy-3,5-di methyl benzyl)-ethylenediamine] with tetra dentate phenol based ligand with N2O2 donor environment along with two labile water molecules was synthesised. The complex (1) is structurally characterized by spectroscopic tools including single-crystal X-ray diffractometer. Complex (1) crystallizes in monoclinic space group P21/n with a = 10.4871(17) Å, b = 20.860 (4) Å and c = 20.955(4) Å. The UV – visible spectra show two peaks around 507 nm and 367 nm due to spin-allowed 1A1g → 1A2g and 1A1g → 1B1g transitions respectively as expected for a square planar d8 system. Mixed ligand octahedral nickel (II) complex with facially coordinating tetra dentate phenol-based ligand (H2L) is in association with two water molecule as ancillary ligand. Two water molecules associated with coordination zone of nickel (II) centre is loosely bound. In this present study, we have evaluated the anti-cancer properties of Complex (1). We found that Complex (1) show potent cancer cell killing activity in case of poorly invasive mice and human cancer cell lines. Complex (1) trigger apoptosis chiefly via p53 dependent pathway. Complex (1) also inhibits cancer cell migration and epithelial to mesenchymal transition in case of metastatic breast cancer cells suggesting potent anti-cancer properties of complex (1).

Abstract PR008: Modulating the PPARγ pathway to augment NECTIN4-targeting chimeric antigen receptor (CAR) T cell therapy

Abstract Background: We present the development of NECTIN4-CAR T cells targeting bladder cancer and evaluate the ability of thiazolidinedione, a class of anti-diabetic drugs, to specifically upregulate NECTIN4 expression and expand the therapeutic window of NECTIN4-CAR T cells. In addition, we assess efficacy of NECTIN4-CAR T cell therapy against a model of bladder cancer with acquired resistance to enfortumab vedotin (EV). Methods: NECTIN4-targeting chimeric antigen receptor (CAR) constructs were designed and cloned into a second-generation EQ-28ζ CAR backbone construct. Human primary T cells were transduced with lentiviral NECTIN4-CAR constructs and co-cultured with a panel of bladder cancer cell lines with a range of NECTIN4 expression and against NECTIN4 knockout cells to assess specificity. Tumor cell count over time was monitored in vitro using an IncuCyte S3. Bladder cancer cell lines (RT112, UMUC-1, HT1197) were treated with PPARγ agonists (rosiglitazone) and antagonists (T0070907), and total and surface NECTIN4 protein levels were assessed. Anti-tumor effects of the NECTIN4-CAR T were evaluated in vitro and in vivo, either with or without rosiglitazone pre-treatment. Finally, RT112 bladder cancer cells were exposed to “cycles” of escalating doses of EV to generate EV-resistant cell line models, and anti-tumor efficacy against EV-resistant lines was evaluated. Results: NECTIN4-targeting CAR T cells displayed potent and NECTIN4-specific cytotoxic activity against bladder cancer cell lines. The efficacy of NECTIN4-CAR T cells was strongly correlated with NECTIN4 expression. Treatment with PPARγ agonists and antagonists was shown to upregulate and downregulate NECTIN4 expression, respectively. Treatment with the PPARγ agonist rosiglitazone induced NECTIN4 expression in a PPARγ-dependent and dose responsive manner. NECTIN4 expression was increased in bladder cancer xenografts established in immunodeficient NSG mice that were treated with systemic rosiglitazone. Priming with rosiglitazone enhanced sensitivity to NECTIN4-CAR T cells in vitro, and the combination of rosiglitazone pre-treatment and NECTIN4-CAR T cell therapy showed enhanced tumor control in bladder cancer xenograft models. We generated RT112 cells that exhibited resistance to EV in vitro and in vivo, which retained NECTIN4 expression. Interestingly, EV-resistant RT112 cells remained sensitive to NECTIN4-CAR T cell therapy both in vitro and in vivo. Conclusions: We engineered a NECTIN4-targeting CAR T cell therapy that is highly antigen-specific and demonstrates antitumor activity against multiple bladder cancer models, including EV resistant cells. Modulating the PPARγ pathway increases NECTIN4 expression, which we leveraged by repurposing an FDA-approved anti-diabetes drug rosiglitazone to increase targeting and anti-tumor efficacy of NECTIN4-CAR T cells. These preclinical results lay the groundwork for CAR T therapy development in bladder cancer and suggest rational drug combinations that can expand the therapeutic window of NECTIN4-targeting therapies. Citation Format: Kevin Chang, Henry M. Delavan, Jun Zhu, Corynn Kasap, Elizabeth Yip, Roshan Lodha, Sheng-You Liao, Sima Porten, Terence Friedlander, Vadim Koshkin, Felix Feng, Arun Wiita, John Lee, Carissa E. Chu, Jonathan Chou. Modulating the PPARγ pathway to augment NECTIN4-targeting chimeric antigen receptor (CAR) T cell therapy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR008.

Enhancing Secondary Metabolite Production in Pelargonium graveolens Hort. Cell Cultures: Eliciting Effects of Chitosan and Jasmonic Acid on Bioactive Compound Production

This study explores the effects of chitosan (CHT) and jasmonic acid (JA) elicitors on rose-scented geranium (Pelargonium graveolens Hort.) cell suspension cultures, aiming to enhance the production of phenolics and flavonoids and antioxidant properties. Elicitation with CHT and JA resulted in varied biomass yields and callus characteristics, with higher concentrations generally leading to increased phenolic accumulation. Optimal biomass was achieved with CHT4 (75 mg/mL) and JA3 (50 µM) treatments. HPLC-DAD analysis revealed changes in phenolic compound composition and quantities, with specific compounds induced by either CHT4 or JA3. For instance, gallic acid content increased significantly in CHT4-treated cells, while catechin content increased notably in both CHT4 and JA3 treatments. Antioxidant enzyme activities like superoxide dismutase and peroxidase increased with elicitor concentration, particularly in CHT4 and JA3 treatments. Both treatments exhibited potent antioxidant activity, with JA3 exhibiting the lowest IC50 value in the DPPH assay and highest total antioxidant capacity (TAC) values. Surprisingly, both CHT4 and JA3 extracts effectively inhibited tyrosinase activity. These findings underscore the efficacy of CHT and JA elicitors in enhancing phenolic and flavonoid production, boosting antioxidant capacity, and inhibiting tyrosinase activity in P. graveolens cultures, offering promising implications for further research and industrial applications in pharmaceutical and cosmetic sectors.

Synthesis and Biological Evaluation of 3-(2-Benzoyl-4-chlorophenyl)-4H-spiro [indole-3,2-[1,3]thiazolidine]-2,4(1H)- dione Derivatives for Anti-tubercular and Antimicrobial Activities

Objectives: To synthesize a new scaff fold of 3'-(2-Benzoyl-4-chlorophenyl)-4'H-spiro [indole-3,2'-[1,3] thiazolidine]-2,4'(1H)-dione derivatives and to assess the compounds for anti-tubercular and antimicrobial activities. Methods : A new series of 3'-(2-Benzoyl-4-chlorophenyl)-4'H-spiro [indole-3,2'- [1,3] thiazolidine]-2,4'(1H)-dione derivatives were prepared by synthesizing schiff’s bases followed by condensing schiff base with 2-mercaptopropanoic acid in the presence of zinc chloride. Synthesized compounds were characterized by IR, NMR and Mass spectral data. Their antimicrobial, antitubercular and also docking simulations were evaluated. Findings : Compound 3c (floro substituent) showed potent activity against Mycobacterium tuberculosis H37Rv with MIC value of 3.125 µg/ml when compared with standard Isoniazid. Compound 3c, 3d and 3f displayed better antimicrobial activity against used bacterial and fungal species with MIC range of 3-20µg/ml comparable to standard drugs ciprofloxacin and ketoconazole respectively. In silico studies revealed that compound 3c, 3f and 3d had a better binding affinity with M. tuberculosis enoyl-CoA hydratase EchA6 with ΔG values of -9.6kcal/mol, -9.4kcal/mol, and -8.6kcal/mol respectively comparable to isoniazid of -5.4kcal/mol. Compound 3c, 3f and 3d also displayed good binding affinity with DNA gyrase and lanosterol methylase. Novelty : Introducing benzoyl moiety to the thiazolidine ring potentiates the antitubercular and antimicrobial activity of spiro indole derivatives. Keywords: AntiTB, Antimicrobial, Molecular Docking, Spiro indole, Thiazolidine

Directed biomechanical compressive forces enhance fusion efficiency in model placental trophoblast cultures.

The syncytiotrophoblast is a multinucleated structure that arises from fusion of mononucleated cytotrophoblasts, to sheath the placental villi and regulate transport across the maternal-fetal interface. Here, we ask whether the dynamic mechanical forces that must arise during villous development might influence fusion, and explore this question using in vitro choriocarcinoma trophoblast models. We demonstrate that mechanical stress patterns arise around sites of localized fusion in cell monolayers, in patterns that match computational predictions of villous morphogenesis. We then externally apply these mechanical stress patterns to cell monolayers and demonstrate that equibiaxial compressive stresses (but not uniaxial or equibiaxial tensile stresses) enhance expression of the syndecan-1 and loss of E-cadherin as markers of fusion. These findings suggest that the mechanical stresses that contribute towards sculpting the placental villi may also impact fusion in the developing tissue. We then extend this concept towards 3D cultures and demonstrate that fusion can be enhanced by applying low isometric compressive stresses to spheroid models, even in the absence of an inducing agent. These results indicate that mechanical stimulation is a potent activator of cellular fusion, suggesting novel avenues to improve experimental reproductive modelling, placental tissue engineering, and understanding disorders of pregnancy development.

Discovery and Structure-Activity Relationship of Cadazolid: A First-In-Class Quinoxolidinone Antibiotic for the Treatment of Clostridioides difficile Infection.

Clostridioides difficile (C. difficile) is one of the leading causes of healthcare-associated infections worldwide. The increasing incidence of strains resistant to currently available therapies highlights the need for alternative treatment options with a novel mode of action. Oxazolidinones that are connected to a quinolone moiety with a pyrrolidine linker, such as compound 1, are reported to exhibit potent broadspectrum antibacterial activity. In an effort to optimize this class of compounds for the treatment of C. difficile infection (CDI), we have identified cadazolid (9), a first-in-class quinoxolidinone antibiotic, which is a potent inhibitor of C. difficile protein synthesis. In order to achieve narrow-spectrum coverage of clinically most relevant strains without affecting the gut microbiota, an emphasis was placed on abolishing activity against commensals of the intestinal microbiome while retaining good coverage of pathogenic C. difficile, including hypervirulent and epidemic strains.

Nickel-doped magnetic carbon aerogel derived from xanthan gum: a competent catalyst for the degradation of single and binary dye-based water pollutants.

Toxic organic dyes (colorants) are one of the main causes of water pollution that releases destructive effluents in the environment. To overcome this issue, a fundamental need to produce a novel, efficient catalyst for the degradation and mineralization of dye mixtures has arisen. The objective of this research is to develop an eminent Ni-doped magnetic carbon aerogel (Ni-MCA) catalyst using graft co-polymerization method having xanthan gum as backbone doped with Ni-magnetic nanoparticles (Ni-MNPs), that do not show agglomeration and easy to separate. The examination revealed that Ni-MCA provided exceptional magnetic characteristics (Ms = 52.75emu/g) and potent catalytic activity for the degradation of mono- as well as binary-dye solutions of Congo red (CR) and methyl green (MG) dyes. The formation was verified by various characterization techniques such as FTIR, VSM, XRD, XPS, SEM, TEM, and EDX mapping. Interestingly, Ni-MCA shows faster result on anionic dye CR up to 97% with degradation rate of 5.647 × 10-1min-1, and MG dye shows degradation of 95.7% with the degradation rate of 2.169 × 10-1min-1, while dye mixture is showing 90% degradation with rate of 2.159 × 10-1min-1.

Abutilon indicum: Bioactive Compounds and Diverse Therapeutic Applications

: A large variety of secondary metabolites are found in medicinal plants, and the majority are significant in medicine. One of the well-known plant species used to cure a wide range of human illnesses is Abutilon indicum. The plant Abutilon indicum has a wide range of therapeutic uses, and its varied parts have been employed to cure a wide range of ailments. Numerous bioactive substances, such as polyphenols, flavonoids, alkaloids, saponins, tannins, and glycosides are present in the plant. Potent antioxidant, anti-inflammatory, antibacterial, hepatoprotective, hypoglycaemic, analgesic, sedative, and diuretic activities have been demonstrated in these compounds. Additionally, the plant has been shown to have cytoprotective properties and to guard against DNA damage brought on by oxidative stress. Future research is required to pinpoint the specific bioactive chemicals responsible for the pharmacological effects of Abutilon indicum and the molecular mechanisms underlying the plant's therapeutic uses. Overall, Abutilon indicum has demonstrated great therapeutic potential and deserves further study as a possible source of homeopathic treatments for various illnesses. The present study covers a summary of the phytochemical and ethnomedicinal applications of Abutilon Indicum that would further help in exploring the research in natural medicine.

Novel 4-Triazole Phenyl Amide (4-TPA) Molecules: Potent Promoters of α-Synuclein Fibril Disassembly

Parkinson's disease profoundly compromises patients' daily lives, and the disassembly of α-synuclein aggregates, a primary pathological factor, represents a promising therapeutic approach. In this study, we conducted a systematic screening and optimization process to identify the novel scaffold B37, a 4-triazolyl-phenylamine derivative, exhibiting a potent disassembly activity of 1.1 μM against α-synuclein preformed fibrils. Notably, B37 demonstrated significant neuroprotective effects, ameliorated autophagic dysfunction induced by preformed fibrils, mitigated oxidative stress, and restored the co-localization of preformed fibrils with lysosomes. Transmission electron microscopy corroborated its in vitro disassembly function. Pharmacokinetic profiling revealed favorable parameters with a receptible blood-brain barrier permeability. B37 emerges as a promising lead compound for further optimization, aiming to develop a highly effective agent targeting the disassembly of α-synuclein aggregates to treat neurodegenerative diseases like Parkinson's disease.

Ginsenoside Rh4 prevents endothelial dysfunction as a novel AMPK activator.

The AMP-activated protein kinase (AMPK) signalling pathway is a desirable target for various cardiovascular diseases (CVD), while the involvement of AMPK-mediated specific downstream pathways and effective interventions in hyperlipidaemia-induced endothelial dysfunction remain largely unknown. Herein, we aim to identify an effective AMPK activator and to explore its efficacy and mechanism against endothelial dysfunction. Molecular docking technique was adopted to screen for the potent AMPK activator among 11 most common rare ginsenosides. In vivo, poloxamer 407 (P407) was used to induce acute hyperlipidaemia in C57BL/6J mice. In vitro, palmitic acid (PA) was used to induce lipid toxicity in HAEC cells. We discovered the strongest binding of ginsenoside Rh4 to AMPKα1 and confirmed the action of Rh4 on AMPK activation. Rh4 effectively attenuated hyperlipidaemia-related endothelial injury and oxidative stress both in vivo and in vitro and restored cell viability, mitochondrial membrane potential and mitochondrial oxygen consumption rate in HAEC cells. Mechanistically, Rh4 bound to AMPKα1 and simultaneously up-regulated AKT/eNOS-mediated NO release, promoted PGC-1α-mediated mitochondrial biogenesis and inhibited P38 MAPK/NFκB-mediated inflammatory responses in both P407-treated mice and PA-treated HAEC cells. The AMPK inhibitor Compound C treatment completely abrogated the regulation of Rh4 on the above pathways and weakened the lowering effect of Rh4 on endothelial impairment markers, suggesting that the beneficial effects of Rh4 are AMPK dependent. Rh4 may serve as a novel AMPK activator to protect against hyperlipidaemia-induced endothelial dysfunction, providing new insights into the prevention and treatment of endothelial injury-associated CVD.

Studies on the Biomimetic Synthesis of Marine Ladder Polyethers via Endo‐Selective Epoxide‐to‐Epoxonium Ring‐Opening Cascades

Marine ladder polyethers have attracted the attention of chemists and biologists because of their potent biological activities. Synthetic chemists have attempted to construct their polyether frameworks by epoxide ring‐opening cascades, as Nakanishi hypothesis describes. However, Baldwin’s rules of ring closure state that exo‐selective intramolecular cyclization of epoxy alcohols is preferred over endo‐selective cyclization. Herein, we investigated epoxide ring‐opening cascades of polyepoxy alcohols in [EMIM]BF4/PFTB (1‐ethyl‐3‐methylimidazolium tetrafluoroborate /perfluoro‐tert‐butyl alcohol) and found that all‐endo products were formed via epoxide‐to‐epoxonium ring‐opening cyclizations (not restricted by Baldwin’s rules, which only apply to intramolecular hydroxyl‐to‐epoxide cyclizations). We determined that the key factor enabling polyepoxy alcohols to undergo a high proportion of all‐endo‐selective cyclizations was inhibition of exo‐selective hydroxyl‐to‐epoxide cyclization starting from the terminal hydroxyl group of a polyepoxy alcohol. By introducing a slow‐release protecting group to the terminal hydroxyl group, we could markedly increase the cyclization yields of polyether fragments with hydrogen atoms at the ring junctions. For the first time, we constructed consecutively fused six‐membered‐ring and fused seven‐, eight‐, and nine‐membered‐ring polyether fragments by epoxide‐to‐epoxonium ring‐opening cyclizations through the addition of a suitable Lewis acid. We also suggest that the biosynthesis of marine ladder polyethers may proceed via epoxide‐to‐epoxonium ring‐opening cyclization of polyepoxide.

Studies on the Biomimetic Synthesis of Marine Ladder Polyethers via Endo-Selective Epoxide-to-Epoxonium Ring-Opening Cascades.

Marine ladder polyethers have attracted the attention of chemists and biologists because of their potent biological activities. Synthetic chemists have attempted to construct their polyether frameworks by epoxide ring-opening cascades, as Nakanishi hypothesis describes. However, Baldwin's rules of ring closure state that exo-selective intramolecular cyclization of epoxy alcohols is preferred over endo-selective cyclization. Herein, we investigated epoxide ring-opening cascades of polyepoxy alcohols in [EMIM]BF4/PFTB (1-ethyl-3-methylimidazolium tetrafluoroborate /perfluoro-tert-butyl alcohol) and found that all-endo products were formed via epoxide-to-epoxonium ring-opening cyclizations (not restricted by Baldwin's rules, which only apply to intramolecular hydroxyl-to-epoxide cyclizations). We determined that the key factor enabling polyepoxy alcohols to undergo a high proportion of all-endo-selective cyclizations was inhibition of exo-selective hydroxyl-to-epoxide cyclization starting from the terminal hydroxyl group of a polyepoxy alcohol. By introducing a slow-release protecting group to the terminal hydroxyl group, we could markedly increase the cyclization yields of polyether fragments with hydrogen atoms at the ring junctions. For the first time, we constructed consecutively fused six-membered-ring and fused seven-, eight-, and nine-membered-ring polyether fragments by epoxide-to-epoxonium ring-opening cyclizations through the addition of a suitable Lewis acid. We also suggest that the biosynthesis of marine ladder polyethers may proceed via epoxide-to-epoxonium ring-opening cyclization of polyepoxide.

A Bispecific Monoclonal Antibody Targeting Psl and PcrV Enhances Neutrophil-Mediated Killing of Pseudomonas aeruginosa in Patients with Bronchiectasis.

Pseudomonas aeruginosa infection is associated with worse outcomes in bronchiectasis. Impaired neutrophil antimicrobial responses contribute to bacterial persistence. Gremubamab is a bivalent, bispecific monoclonal antibody targeting Psl exopolysaccharide and the type 3 secretion system component PcrV. This study evaluated the efficacy of gremubamab to enhance killing of P.aeruginosa by neutrophils from bronchiectasis patients and to prevent P.aeruginosa-associated cytotoxicity. P.aeruginosa isolates from a global bronchiectasis cohort (n=100) underwent whole-genome sequencing to determine target prevalence. Functional activity of gremubamab against selected isolates was tested in-vitro and in-vivo. Patients with bronchiectasis (n=11) and controls (n=10) were enrolled and the effect of gremubamab in peripheral-blood neutrophil opsonophagocytic killing (OPK) assays against P.aeruginosa was evaluated. Serum antibody titers to Psl and PcrV were determined (n=30; 19: chronic P.aeruginosa infection, 11: no-known P.aeruginosa infection), as was the effect of gremubamab treatment in OPK and anti-cytotoxic activity assays. Psl and PcrV were conserved in isolates from chronically-infected bronchiectasis patients. 73/100 isolates had a full psl locus and 99/100 contained the pcrV gene, with 20 distinct full-length PcrV protein subtypes identified. PcrV subtypes were successfully bound by gremubamab and the mAb mediated potent protective activity against tested isolates. Gremubamab increased bronchiectasis patient neutrophil-mediated OPK (+34.6±8.1%) and phagocytosis (+70.0±48.8%), similar to effects observed in neutrophils from controls (OPK:+30.1±7.6%). No evidence of competition between gremubamab and endogenous antibodies was found, with protection against P.aeruginosa-induced cytotoxicity and enhanced OPK demonstrated with and without addition of patient serum. Gremubamab enhanced bronchiectasis patient neutrophil phagocytosis and killing of P.aeruginosa and reduced virulence.

Antibacterial activity of pimaradienoic acid from Eleutherococcus trifoliatus (L.) S. Y. Hu.

Purpose: To investigate the antibacterial activity of pimaradienoic acid, a natural product isolated from Eleutherococcus trifoliatus. Methods: Pimaradienoic acid was purified from E. trifoliatus and tested against three Gram-positive bacteria. Minimum inhibitory concentrations (MICs) were determined, and bacterial growth curves were measured. Scanning electron microscopy (SEM) was used to observe morphological changes in bacteria after drug treatment. Results: Pimaradienoic acid exhibited concentration-dependent inhibition of the growth of the three bacteria tested. The MIC and bacterial growth dynamics results indicated that pimaradienoic acid had potent antibacterial activity. SEM revealed that pimaradienoic acid disrupted the bacterial membrane, leading to cell death. Conclusions: Pimaradienoic acid has significant antibacterial activity against Gram-positive bacteria, suggesting its potential as a novel antimicrobial agent.