The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl-Acyl Carrier Protein Binding Site of FabI

The enoyl-acyl carrier protein reductase enzyme FabI is essential for fatty acid biosynthesis in Staphylococcus aureus and represents a promising target for the development of novel, urgently needed anti-staphylococcal agents. Here, we elucidate the mode of action of the kalimantacin antibiotics, a novel class of FabI inhibitors with clinically-relevant activity against multidrug-resistant S. aureus. By combining X-ray crystallography with molecular dynamics simulations, in vitro kinetic studies and chemical derivatization experiments, we characterize the interaction between the antibiotics and their target, and we demonstrate that the kalimantacins bind in a unique conformation that differs significantly from the binding mode of other known FabI inhibitors. We also investigate mechanisms of acquired resistance in S. aureus and identify key residues in FabI that stabilize the binding of the antibiotics. Our findings provide intriguing insights into the mode of action of a novel class of FabI inhibitors that will inspire future anti-staphylococcal drug development.     

An Fe2+- and α-Ketoglutarate-Dependent Halogenase Acts on Nucleotide Substrates

While halogenated nucleosides are used as common anticancer and antiviral drugs, naturally occurring halogenated nucleosides are rare. Adechlorin (ade) is a 2′-chloro nucleoside natural product first identified from Actinomadura sp. ATCC 39365. However, the installation of chlorine in the ade biosynthetic pathway remains elusive. Reported herein is a Fe²⁺-α-ketoglutarate halogenase AdeV that can install a chlorine atom at the C2′ position of 2′-deoxyadenosine monophosphate to afford 2′-chloro-2′-deoxyadenosine monophosphate. Furthermore, 2′,3′-dideoxyadenosine-5′-monophosphate and 2′-deoxyinosine-5′-monophosphate can also be converted, albeit 20-fold and 2-fold, respectively, less efficiently relative to the conversion of 2′-deoxyadenosine monophosphate. AdeV represents the first example of a Fe²⁺-α-ketoglutarate-dependent halogenase that converts nucleotides into chlorinated analogues.     

高效液相色谱-质谱联用法同步测定城市污水处理厂活性污泥中的多类抗生素残留

采用超声萃取、固相萃取及高效液相色谱-质谱联用技术(LC-MS),建立了活性污泥中3类共9种抗生素(包括5种磺胺类、3种四环素类及1种大环内酯类)的同时分析方法.样品经甲醇-Na2,EDTA/Mcllvaine缓冲液(1∶1,体积比)超声萃取,HLB固相萃取柱净化富集后,以Symmetry C18反相柱为分析柱,0.2...     

A Spectrophotometric Study of Streptomycin Effect on the Clinical Urea Determination

The results of studying inhibitory effect of streptomycin on the modified Berthelot reaction were presented in this paper and a new kinetic method for determining streptomycin in pharmaceutical preparations and human urine was developed on the basis of the obtained results. The rates of catalytic and catalytic‐inhibitory reaction were monitored at 700 nm (t=25±0.1°C) using UV/vis spectrophotometer. By analyzing the spectra and experimental dependences of the catalytic and catalytic‐inhibitory reaction rates on the reactant concentrations, it was noticed that streptomycin attacked nitroprusside and hypochlorite causing the inhibition of the production of 2,2′‐dicarboxylindophenol. According to this effect, an analytical decrease for determination of urea by modified Berthelot reaction appeared in the presence of small amounts of streptomycin. Beer's law was obeyed in the interval of streptomycin sulfate concentration from 18.2 to 182 µg·mL^?1. The detection limit calculated by two methods was obtained at 11.75 µg·mL^?1 and 8.54 µg·mL^?1. The relative standard deviation of 0.55%–8.83% and the recovery of 109.10% were determined. The obtained results were validated using the referent HPLC method.     

Preparation of hydrophilic molecularly imprinted polymers for tetracycline antibiotics recognition

Hydrophilic molecularly imprinted polymers(MIPs) were prepared using tetracycline as template,methacrylic acid as monomer and glycidilmethacrylate as pro-hydrophilic co-monomer.Compared with common MIPs,the imprinting effect and adsorption amounts of hydrophilic MIPs for tetracycline(TC) were greatly improved in water media.Furthermore,the electrochemical sensor fabricated by modifying hydrophilic MIPs on glassy carbon electrode was developed for the determination of TC in foodstuff samples.     

Direct Assembly of 2‐Oxazolidinones by Chemical Fixation of Carbon Dioxide

The reaction of β‐ and γ‐haloamines with carbon dioxide to give pharmaceutically relevant 2‐oxazolidinones and 1,3‐dioxazin‐2‐ones, was found to proceed efficiently in the presence of a base and in the absence of catalyst. After optimization of reaction conditions, the system was successfully expanded to a variety of haloamines, even at multigram scale. The reaction was further studied in silico by DFT calculations.     

Rapid colorimetric sensing of tetracycline antibiotics with in situ growth of gold nanoparticles

A colorimetric assay utilizing the formation of gold nanoparticles was developed to detect tetracycline antibiotics in fluidic samples. Tetracycline antibiotics showed the capability of directly reducing aurate salts into atomic gold which form gold nanoparticles spontaneously under proper conditions. The resulted gold nanoparticles showed characteristic plasmon absorbance at 526 nm, which can be visualized by naked eyes or with a spectrophotometer. UV–vis absorbance of the resulted gold nanoparticles is correlated directly with the concentrations of tetracycline antibiotics in the solution, allowing for quantitative colorimetric detection of tetracycline antibiotics. Reaction conditions, such as pH, temperature, reaction time, and ionic strength were optimized. Sensitivity of the colorimetric assay can be enhanced by the addition of gold nanoparticle seeds, a LOD as low as 20 ng mL⁻¹ can be achieved with the help of seed particles. The colorimetric assay showed minimum interference from ethanol, methanol, urea, glucose, and other antibiotics such as sulfonamides, amino glycosides etc. Validity of the method was also evaluated on urine samples spiked with tetracycline antibiotics. The method provides a broad spectrum detection method for rapid and sensitive detection of reductive substances such as tetracycline antibiotics in liquid and biological samples.     

荧光光度法测定头孢菌素类抗生素含量的研究进展

对近40年来利用荧光光度法测定头孢菌素类抗生素的研究进展进行了综述,包括利用药物酸性或碱性降解产物的荧光光度法、利用药物与金属离子的氧化还原和络合作用的荧光光度法和利用药物与有机荧光试剂反应的荧光光度法(引用文献30篇)。     

HPLC-RRS联用技术在抗生素药物分析中的应用及进展

共振瑞利散射(RRS)是近年来发展起来的一种灵敏度高和操作简单的光谱分析技术。高效液相色谱—共振瑞利散射(HPLC-RRS)联用技术是以高效液相色谱为分离手段,以共振瑞利散射为鉴定工具的一种分离分析技术。本文综述了国内近年来高效液相色谱—共振瑞利散射联用技术在抗生素类药物分析中的应用,并对该方法今后的发展进行展望。     

Synthesis and Absolute Configuration of Demethyl (C‐11) Cezomycin

The synthesis of (?)‐demethyl (C‐11) cezomycin was achieved through an efficient route that features the use of a Kulinkovich reaction to couple two multifunctionality‐containing fragments and a cascade of ring opening of cyclopropanol/1,5‐hydrogen shift/desilylation–oxidation. The hidden yet undeniable problem of irreproducible specific rotation for this family of compounds was solved by sufficient acidification. The absolute configuration for the natural product was thus established as the mirror image of the synthetic sample.