Teixobactin has been the source of intensive study and interest as a promising antibiotic, because of its excellent activity against drug-resistant Gram-positive pathogens and its novel but not yet fully understood mechanism of action that precludes drug resistance. Recent studies have demonstrated that the mode of action of teixobactin is more complicated than initially thought, with supramolecular assembly of the antibiotic appearing to play a critical role in the binding process. Further studies of the interactions of teixobactin with bacteria and its molecular targets offer the promise of providing deeper insights into its novel mechanism of action and guiding the design of additional drug candidates and analogues. The current study reports the preparation and study of teixobactin analogues bearing a variety of fluorophores. Structured illumination microscopy of the fluorescent teixobactin analogues with B. subtilis enables super-resolution visualization of the interaction of teixobactin with bacterial cell walls and permits the observation of aggregated clusters of the antibiotic on the bacteria. Förster resonance energy transfer (FRET) microscopy further elucidates the supramolecular assembly by showing that fluorescent teixobactin molecules co-localize within a few nanometers on B. subtilis. Fluorescence microscopy over time with a fluorescent teixobactin analogue and propidium iodide in B. subtilis reveals a correlation between cell death and binding of the antibiotic to cellular targets, followed by lysis of cells. Collectively, these studies provide new insights into the binding of teixobactin to Gram-positive bacteria, its supramolecular mechanism of action, and the lysis of bacteria that follows.FRET microscopy experiments demonstrate supramolecular assembly of teixobactin molecules on Bacillus subtilis, providing further evidence that teixobactin is a supramolecular antibiotic.相似文献
Commercial poly(vinylalcohol) samples (PVOH) of average molecular mass (Mw) 120,000 g/mol, were subjected to biodegradation with enzymatic extracts of the Phanerochaete chrysosporium fungus, in which the lignine peroxidase activity (LiP) was detected. The results of differential refractive index and ultraviolet (UV) absorption Gel Permeation Chromatography (GPC), Fourier Transform Infrared Spectroscopy (FTIR) and Gas Chromatography coupled to a Mass Detector (GC-MS) allow to deduce that in 15 days, under the conditions of this study, the average molar mass of the polymer decreases in 79.3 %. The benzaldehyde was detected as the main degradation product. 相似文献
Guanine nucleotide exchange factors (GEFs) and their target Rho GTPases regulate cytoskeletal changes and membrane trafficking.
Dynamin, a large force-generating GTPase, plays an essential role in membrane tubulation and fission in cells. Kalirin12,
a neuronal RhoGEF, is found in growth cones early in development and in dendritic spines later in development. 相似文献
Vitamin A deficiency continues to be a major public health concern in the developing world effecting over 200 million people. Interventions including carotenoid-rich fruits and vegetables, containing α- and β-carotene, and β-cryptoxanthin, are being tested for their potential to alleviate vitamin A deficiency in several countries. Thus, there is a need for a faster isocratic reverse-phase high pressure liquid chromatography (HPLC) method than the methods currently available. Efficient extraction procedures for biological samples are also valuable to save time, materials, and cost. We developed an HPLC method and compared several extraction methods for carotenoids, retinoids, and vitamin E in plasma and human breast milk. The method uses an Agilent 1100 system equipped with a Waters Spherisorb ODS2 column (3 × 125 mm 3 μm) and similar guard column (ThermoScientific ODS2 3 × 20 mm 3 μm). Mobile phase of 7:2:1 acetonitrile:dichloromethane:methanol was run at 0.5 mL min−1, and run times were complete in approximately 8 min. This rapid method uses little solvent and provides excellent results in the analysis of these fat-soluble nutrients. Analyte measurements were repeatable using standards and plasma and were accurate compared to NIST certified and reference serum values. The validated HPLC method was applied to the analysis of plasma samples from a vitamin A intervention study.
Lysine‐specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A‐tri‐/di‐methylated histone 3 protein–protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple‐negative breast cancer (TNBC) cell lines, MDA‐MB‐231 and 4T1. Finally, 1 exhibited potent anti‐tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal‐based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC. 相似文献
Commercial copolymers of 1‐octene and ethylene: metallocene catalyzed (mLLDPE) and Ziegler‐Natta catalyzed (znLLDPE), a low density polyethylene (LDPE), and high density polyethylene (HDPE), were characterized with respect to branching, crystallization behaviour and dynamic‐mechanical properties. It was found that the crystallinity of the polymers is more influenced by the homogeneity of the short‐chain branching than by its content. The study of blends of mLLDPE and znLLDPE with LDPE and HDPE showed that the interaction between mLLDPE and LDPE is stronger than between znLLDPE and LDPE. Blends containing mLLDPE showed a composition depending improvement of the storage modulus G' which was not observed in znLLDPE/LDPE blends. The HPDE blends followed a linear mixing rule. Co‐crystallization was found mLLDPE/LDPE and partially in znLLDPE/LDPE and znLLDPE/HDPE blends, respectively. 相似文献
Fully optimized geometries are reported for two possible isomers of B4H10. At the restricted Hartree-Fock level, the unobserved bisdiborane isomer is lower in energy than the observed isomer. Generalized-molecular-orbital, configuration-interaction calculations show that electron correlation is responsible for this reversal. Electron correlation may be important in stabilizing other cluster molecules. 相似文献