Search Results (24)

Background: The role of the indoor microbiome in sick building syndrome (SBS) is well-recognized, yet prior studies have been limited to single-center analyses, limiting a broader understanding and applicability of their findings. Methods: We conducted a multicenter indoor microbiome and metabolome investigation for SBS, involving 1139 middle school students across three regions in Malaysia (Johor Bahru, Terengganu, and Penang). Using high-throughput amplicon sequencing and untargeted LC-MS, indoor microbiome and metabolites were characterized from classroom dust samples. Results: The study found that the prevalence of SBS symptoms was high across all three centers (51.0% to 54.6%). Environmental characteristics, including indoor NO₂ and CO₂ concentrations and total weight of indoor dust, were positively associated with SBS (p < 0.01, linear regression). Curtobacterium in Terengganu was negatively associated with SBS, and Clostridium perfringens in Johor Bahru was positively associated with SBS (p < 0.01, FDR < 0.05). Whereas all identified fungal taxa, including an uncharacterized uc_f_Auriculariaceae_sp., Duportella kuehneroides, and Wallemia mellicola, were positively associated with SBS (p < 0.01, FDR < 0.05) in Johor Bahru and Terengganu. Mediation analysis revealed that the adverse health effects of NO₂ on SBS were partially mediated by the increased abundance of uc_f_Auriculariaceae_sp. (p < 0.05, total effect mediated 51.40%). Additionally, potential protective metabolites (S-adenosylmethionine, N-acetylserotonin, sphinganine, 4-hydroxy-2-quinolone, and (2E,4Z,8E)-Colneleic acid) were mainly derived from environmental microorganisms, conferring protective effects against nasal symptoms and tiredness. In contrast, synthetic chemicals were associated with higher SBS symptoms, inducing eye and nasal symptoms. Conclusions: This study emphasizes both the significance of fostering a balanced indoor microbiome/metabolite and the necessity to reduce exposure to deleterious substances, providing new insights for future targeted intervention strategies. Full article

Background: Dysregulation in phosphoinositide-3-kinase alpha (PI3Kα) signaling is implicated in the development of various cancers, including triple-negative breast cancer (TNBC). We have previously synthesized a series of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides as targeted inhibitors against PI3Kα. Herein, two drug candidates, R7 and R11, were selected to be further investigated as a nanoparticle (NP) formulation against TNBC. Methods: R7 and R11 were entrapped in D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) polymeric NPs by nanoprecipitation. Following their physicochemical characterization, the anticancer activity of the compounds and their NP formulations was evaluated in the TNBC cell line MDA-MB-231 by conducting viability, uptake, and apoptosis assays, as well as penetration assays in a multicellular tumor spheroid model. Results: The NPs exhibited a particle size of 100–200 nm, excellent drug loading efficiencies, and sustained release under physiologic conditions. Viability assays revealed superior potency for the NP formulations, with IC₅₀ values of 20 µM and 30 µM for R7- and R11-loaded NPs, respectively, compared to the free compounds, which exhibited IC₅₀ values of 280 µM and 290 µM for R7 and R11, respectively. These results were attributed to the inherent antiproliferative activity of TPGS, as evidenced by the cytotoxicity of the drug-free NPs, as well as the enhanced cellular uptake enabled by the NP vehicle, as demonstrated by fluorescence microscopy imaging and flow cytometry measurements. Further investigations showed that the NPs promoted apoptosis via a mitochondrial-dependent pathway that involved the activation of proapoptotic caspases. Moreover, the NP formulations enhanced the penetration ability of the free compounds in multicellular tumor spheroids, causing a time- and concentration-dependent disruption of the spheroids. Conclusions: Our findings highlight the important role nanotechnology can play in improving the biopharmaceutical properties of new drug candidates and facilitating their in vivo translation. Full article

Pseudomonas aeruginosa is an opportunistic pathogen that requires iron to survive in the host; however, the host immune system limits the availability of iron. Pyochelin (PCH) is a major siderophore produced by P. aeruginosa during infection, which can help P. aeruginosa survive in an iron-restricted environment and cause infection. The infection activity of P. aeruginosa is regulated by the Pseudomonas quinolone signal (PQS) quorum-sensing system. The system uses 2-heptyl-3-hydroxy-4-quinolone (PQS) or its precursor, 2-heptyl-4-quinolone (HHQ), as the signal molecule. PQS can control specific life processes such as mediating quorum sensing, cytotoxicity, and iron acquisition. This review summarizes the biosynthesis of PCH and PQS, the shared transport system of PCH and PQS, and the regulatory relationship between PCH and PQS. The correlation between the PQS and PCH is emphasized to provide a new direction for future research. Full article

Characterizing molecular interactions at the microscopic level remains difficult and, therefore, represents a key target to better understand macromolecule and biomacromolecule behaviors in solution, alone, or in mixtures with others. Therefore, accurate characterization in liquid media, especially in aqueous solutions, without causing any perturbation of the system in which they are studied, is quite difficult. To this purpose, the present paper describes an innovative methodology based on fluorescence spectrophotometry. Two molecular fluorescent probes, namely 8-anilino-1-naphtalenesulfonic acid (ANS) and 2-benzofuryl-3-hydroxy-4(1H)-quinolone (3HQ-Bf), were selected to characterize, respectively, the dipole-dipole interactions and hydrophobic micro-domains, for the first one, and hydrogen bonding, for the second. As a support to study molecular interactions, xanthan, galactomannan, and corresponding mixtures of these substances which are well known to exhibit a synergy of interactions in well-defined mixture conditions were chosen. Once the methodology was set up, the existence of the three types of interactions in these systems was demonstrated, thus allowing the elucidation of the mechanisms of interactions at the molecular scale. Full article

In the search for new potential drug candidates acting as anticancer agents, we were interested in a small molecule derived from 4-hydroxy-2-quinolone, which is newly synthesized from the condensation of a β-enaminone and diethylmalonate under microwave irradiation. This compound was subjected to an in silico study in order to investigate its potentiality to act against lung cancer through inhibiting a tyrosine kinase: Anaplastic Lymphoma Kinase (ALK). A docking simulation was performed in the active pocket of the human ALK complexed with a commercialized anticancer agent—Entrectinib (Pdb: 5FTO)—using Schrodinger suite. The studied derivative showed good stability inside the active site with an estimated docking score equal to −8.054 kcal·mol⁻¹. In addition, significant interactions, similar to those formed by the co-crystallized ligand, were present in the studied compound, counting hydrogen bonds with Met1199 and Glu1197 as well as hydrophobic contacts with residues in the cavity of the ALK. Keeping in mind that the pharmacokinetic properties and the toxicity of a drug candidate are very important factors in conceiving a safe admissible therapeutic substance, we carried out an ADMET prediction for the studied molecules using SwissADME, MolSoft, and ProTox-II, which gave promising results. Full article

Although 1-hydroxy-4-quinolone derivatives, such as 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO), aurachin C, and floxacrine, have been reported as effective cytochrome bc₁ complex inhibitors, the bioactivity of these products is not ideal, presumably due to their low bioavailability in tissues, particularly their poor solubility and low mitochondrial accumulation. In order to overcome the drawbacks of these compounds and develop their use as agricultural fungicides acting by cytochrome bc₁ inhibition, in this study, three novel mitochondria-targeting quinolone analogs (mitoQNOs) were designed and synthesized by conjugating triphenylphosphonium (TPP) with quinolone. They exhibited greatly enhanced fungicidal activity compared to the parent molecule, especially mitoQNO₁₁, which showed high antifungal activity against Phytophthora capsici and Sclerotinia sclerotiorum with EC₅₀ values of 7.42 and 4.43 μmol/L, respectively. In addition, mitoQNO₁₁ could inhibit the activity of the cytochrome bc₁ complex of P. capsici in a dose-dependent manner and effectively depress its respiration and ATP production. The greatly decreased mitochondrial membrane potential and massively generated reactive oxygen species (ROS) strongly suggested that the inhibition of complex III led to the leakage of free electrons, which resulted in the damage of the pathogen cell structure. The results of this study indicated that TPP-conjugated QNOs might be used as agricultural fungicides by conjugating them with TPP. Full article

Sustainable functionalization of renewable aromatics is a key step to supply our present needs for specialty chemicals and pursuing the transition to a circular, fossil-free economy. In the present work, three typically stable aromatic compounds, representative of products abundantly obtainable from biomass or recycling processes, were functionalized in one-pot oxidation reactions at room temperature, using H₂O₂ as a green oxidant and ethanol as a green solvent in the presence of a highly electron withdrawing iron porphyrin catalyst. The results show unusual initial epoxidation of the aromatic ring by the green catalytic system. The epoxides were isolated or evolved through rearrangement, ring opening by nucleophiles, and oxidation. Acridine was oxidized to mono- and di-oxides in the peripheral ring: 1:2-epoxy-1,2-dihydroacridine and anti-1:2,3:4-diepoxy-1,2,3,4-tetrahydroacridine, with TON of 285. o-Xylene was oxidized to 4-hydroxy-3,4-dimethylcyclohexa-2,5-dienone, an attractive building block for synthesis, and 3,4-dimethylphenol as an intermediate, with TON of 237. Quinoline was directly functionalized to 4-quinolone or 3-substituted-4-quinolones (3-ethoxy-4-quinolone or 3-hydroxy-4-quinolone) and corresponding hydroxy-tautomers, with TON of 61. Full article

The opportunistic pathogen Pseudomonas aeruginosa uses quorum sensing to control its virulence. One of its major signal molecules, the Pseudomonas quinolone signal PQS, has high affinity to membranes and is known to be trafficked mainly via outer membrane vesicles (OMVs). We previously reported that several 3-hydroxy-4(1H)-quinolone 2,4-dioxygenases (HQDs) catalyze the cleavage of PQS and thus act as quorum quenching enzymes. Further analysis showed that, in contrast to other HQDs, the activity of HQD from Streptomyces bingchenggensis (HQD_S._b.) was unexpectedly stabilized by culture supernatants of P. aeruginosa. Interestingly, the stabilizing effect was higher with supernatants from the strain PA14 than with supernatants from the strain PAO1. Heat treatment and lyophilization hardly affected the stabilizing effect; however, fractionation of the supernatant excluded small molecules as stabilizing agents. In a pull-down assay, HQD_S._b. appeared to interact with several P. aeruginosa proteins previously found in the OMV proteome. This prompted us to probe the physical interaction of HQD_S._b. with prepared extracellular membrane vesicles. Homo-FRET of fluorescently labeled HQD_S._b. indeed indicated a spatial clustering of the protein on the vesicles. Binding of a PQS-cleaving enzyme to the OMVs of P. aeruginosa may enhance PQS degradation and is highly reconcilable with its function as a quorum quenching enzyme. Full article

N-(2-fluorphenyl)-6-chloro-4-hydroxy-2-quinolone-3-carboxamide (R19) is a newly synthesized phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor with promising activity against cancer cells. The purpose of this study was to develop a polymeric nanoparticle (NP) formulation for R19 to address its poor aqueous solubility and to facilitate its future administration in preclinical and clinical settings. NPs were prepared by nanoprecipitation using two polymers: D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and the poloxamer Pluronic P123 in different ratios. Physicochemical characterization of the NPs revealed them to be around 100 nm in size with high monodispersity, a spherical morphology, and an almost neutral surface charge. The NPs achieved ~60% drug loading efficiency and sustained release of R19 for up to 96 h, with excellent colloidal stability in serum-containing cell culture media. NPs containing TPGS enhanced R19’s potency against MCF-7 and MDA-MB-231 breast cancer cells in vitro, with half-maximal inhibitory concentrations (IC₅₀) ranging between 1.8 and 4.3 µM compared to free R19, which had an IC₅₀ of 14.7–17.0 µM. The NPs also demonstrated low cytotoxicity against human dermal fibroblasts and more significant induction of apoptosis compared to the free drug, which was correlated with their cellular uptake efficiency. Our findings present a biocompatible NP formulation for the delivery of a cancer-targeted PI3Kα inhibitor, R19, which can further enhance its potency for the treatment of breast cancer and potentially other cancer types. Full article

The opportunistic pathogen Pseudomonas aeruginosa employs quorum sensing to govern the production of many virulence factors. Interference with quorum sensing signaling has therefore been put forward as an attractive approach to disarm this pathogen. Here, we analyzed the quorum quenching properties of natural and engineered (2-alkyl-)3-hydroxy-4(1H)-quinolone 2,4-dioxygenases (HQDs) that inactivate the P. aeruginosa signal molecule PQS (Pseudomonas quinolone signal; 2-heptyl-3-hydroxy-4(1H)-quinolone). When added exogenously to P. aeruginosa cultures, all HQDs tested significantly reduced the levels of PQS and other alkylquinolone-type secondary metabolites deriving from the biosynthetic pathway, such as the respiratory inhibitor 2-heptyl-4-hydroxyquinoline N-oxide. HQDs from Nocardia farcinica and Streptomyces bingchenggensis, which combine low K_M values for PQS with thermal stability and resilience in the presence of P. aeruginosa exoproducts, respectively, attenuated production of the virulence factors pyocyanin and pyoverdine. A delay in mortality was observed when Galleria mellonella larvae were infected with P. aeruginosa suspensions treated with the S. bingchenggensis HQD or with inhibitors of alkylquinolone biosynthesis. Our data indicate that quenching of PQS signaling has potential as an anti-virulence strategy; however, an efficient anti-virulence therapy against P. aeruginosa likely requires a combination of agents addressing multiple targets. Full article

Cancer is a multifactorial disease and the second leading cause of death worldwide. Diverse factors induce carcinogenesis, such as diet, smoking, radiation, and genetic defects. The phosphatidylinositol 3-kinase (PI3Kα) has emerged as an attractive target for anticancer drug design. Eighteen derivatives of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide were synthesized and characterized using FT-IR, NMR (¹H and ¹³C), and high-resolution mass spectra (HRMS). The series exhibited distinct antiproliferative activity (IC₅₀ µM) against human epithelial colorectal adenocarcinoma (Caco-2) and colon carcinoma (HCT-116) cell lines, respectively: compounds 16 (37.4, 8.9 µM), 18 (50.9, 3.3 µM), 19 (17.0, 5.3 µM), and 21 (18.9, 4.9 µM). The induced-fit docking (IFD) studies against PI3Kαs showed that the derivatives occupy the PI3Kα binding site and engage with key binding residues. Full article

The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (¹H and ¹³C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds 8 (IC₅₀ Caco-2 = 98 µM, IC₅₀ HCT-116 = 337 µM) and 16 (IC₅₀ Caco-2 = 13 µM, IC₅₀ HCT-116 = 240.2 µM). Results showed that compound 16 significantly affected the gene encoding AKT, BAD, and PI3K. The induced-fit docking (IFD) studies against PI3Kα demonstrated that the scaffold accommodates the kinase domains and forms H-bonds with significant binding residues. Full article

Pseudomonas aeruginosa is a ubiquitous environmental bacterium that causes chronic infections of burn wounds and in the lungs of cystic fibrosis (CF) patients. Vital to its infection is a myriad of specialized metabolites that serve a variety of biological roles including quorum sensing, metal chelation and inhibition of other competing bacteria. This study employed newly available algorithms for searching individual tandem mass (MS/MS) spectra against the publicly available Global Natural Product Social Molecular Networking (GNPS) database to identify the chemical diversity of these compounds and their presence in environmental, laboratory and clinical samples. For initial characterization, the metabolomes of eight clinical isolates of P. aeruginosa were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and uploaded to GNPS for spectral searching. Quinolones, rhamnolipids, phenazines and siderophores were identified and characterized; including the discovery of modified forms of the iron chelator pyochelin. Quinolones were highly diverse with the three base forms Pseudomonas quinolone signal 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), 4-heptyl-4(1H)-quinolone (HHQ) and 2-heptyl-4-quinolone-N-oxide (HQNO) having extensive variation in the length of their acyl chain from as small as 3 carbons to as large as 17. Rhamnolipids were limited to either one or two sugars with a limited set of fatty acyl chains, but the base lipid form without the rhamnose was also detected. These specialized metabolites were identified from diverse sources including ant-fungal mutualist dens, soil, plants, human teeth, feces, various lung mucus samples and cultured laboratory isolates. Their prevalence in fecal samples was particularly notable as P. aeruginosa is not known as a common colonizer of the human gut. The chemical diversity of the compounds identified, particularly the quinolones, demonstrates a broad spectrum of chemical properties within these the metabolite groups with likely significant impacts on their biological functions. Mining public data with GNPS enables a new approach to characterize the chemical diversity of biological organisms, which includes enabling the discovery of new chemistry from pathogenic bacteria. Full article

A library of 23 pure compounds of varying structural and chemical characteristics was screened for their quorum sensing (QS) inhibition activity using a synthetic fluorescent Escherichia coli biosensor that incorporates a modified version of lux regulon of Vibrio fischeri. Four such compounds exhibited QS inhibition activity without compromising bacterial growth, namely, phenazine carboxylic acid (PCA), 2-heptyl-3-hydroxy-4-quinolone (PQS), 1H-2-methyl-4-quinolone (MOQ) and genipin. When applied at 50 µM, these compounds reduced the QS response of the biosensor to 33.7% ± 2.6%, 43.1% ± 2.7%, 62.2% ± 6.3% and 43.3% ± 1.2%, respectively. A series of compounds only showed activity when tested at higher concentrations. This was the case of caffeine, which, when applied at 1 mM, reduced the QS to 47% ± 4.2%. In turn, capsaicin, caffeic acid phenethyl ester (CAPE), furanone and polygodial exhibited antibacterial activity when applied at 1mM, and reduced the bacterial growth by 12.8% ± 10.1%, 24.4% ± 7.0%, 91.4% ± 7.4% and 97.5% ± 3.8%, respectively. Similarly, we confirmed that trans-cinnamaldehyde and vanillin, when tested at 1 mM, reduced the QS response to 68.3% ± 4.9% and 27.1% ± 7.4%, respectively, though at the expense of concomitantly reducing cell growth by 18.6% ± 2.5% and 16% ± 2.2%, respectively. Two QS natural compounds of Pseudomonas aeruginosa, namely PQS and PCA, and the related, synthetic compounds MOQ, 1H-3-hydroxyl-4-quinolone (HOQ) and 1H-2-methyl-3-hydroxyl-4-quinolone (MHOQ) were used in molecular docking studies with the binding domain of the QS receptor TraR as a target. We offer here a general interpretation of structure-function relationships in this class of compounds that underpins their potential application as alternatives to antibiotics in controlling bacterial virulence. Full article

Alkyl quinolone has been proven to be a privileged scaffold in the antimicrobial drug discovery pipeline. In this study, a series of new 4-hydroxy-2-quinolinone analogs containing a long alkyl side chain at C-3 and a broad range of substituents on the C-6 and C-7 positions were synthesized. The antibacterial and antifungal activities of these analogs against Staphylococcus aureus, Escherichia coli, and Aspergillus flavus were investigated. The structure-activity relationship study revealed that the length of the alkyl chain, as well as the type of substituent, has a dramatic impact on the antimicrobial activities. Particularly, the brominated analogs 3j with a nonyl side chain exhibited exceptional antifungal activities against A. flavus (half maximal inhibitory concentration (IC₅₀) = 1.05 µg/mL), which surpassed that of the amphotericin B used as a positive control. The antibacterial activity against S. aureus, although not as potent, showed a similar trend to the antifungal activity. The data suggest that the 4-hydroxy-2-quinolone is a promising framework for the further development of new antimicrobial agents, especially for antifungal treatment. Full article