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141.
142.
Dr. Luke A. Clifton Dr. Stephen A. Holt Dr. Arwel V. Hughes Dr. Emma L. Daulton Dr. Wanatchaporn Arunmanee Dr. Frank Heinrich Dr. Syma Khalid Damien Jefferies Dr. Timothy R. Charlton Dr. John R. P. Webster Dr. Christian J. Kinane Prof. Jeremy H. Lakey 《Angewandte Chemie (International ed. in English)》2015,54(41):11952-11955
Gram‐negative bacteria are an increasingly serious source of antibiotic‐resistant infections, partly owing to their characteristic protective envelope. This complex, 20 nm thick barrier includes a highly impermeable, asymmetric bilayer outer membrane (OM), which plays a pivotal role in resisting antibacterial chemotherapy. Nevertheless, the OM molecular structure and its dynamics are poorly understood because the structure is difficult to recreate or study in vitro. The successful formation and characterization of a fully asymmetric model envelope using Langmuir–Blodgett and Langmuir–Schaefer methods is now reported. Neutron reflectivity and isotopic labeling confirmed the expected structure and asymmetry and showed that experiments with antibacterial proteins reproduced published in vivo behavior. By closely recreating natural OM behavior, this model provides a much needed robust system for antibiotic development. 相似文献
143.
Membrane Disruption and Enhanced Inhibition of Cell‐Wall Biosynthesis: A Synergistic Approach to Tackle Vancomycin‐Resistant Bacteria
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Venkateswarlu Yarlagadda Dr. Sandip Samaddar Dr. Krishnamoorthy Paramanandham Dr. Bibek R. Shome Dr. Jayanta Haldar 《Angewandte Chemie (International ed. in English)》2015,54(46):13644-13649
Resistance to glycopeptide antibiotics, the drugs of choice for life‐threatening bacterial infections, is on the rise. In order to counter the threat of glycopeptide‐resistant bacteria, we report development of a new class of semi‐synthetic glycopeptide antibiotics, which not only target the bacterial membrane but also display enhanced inhibition of cell‐wall biosynthesis through increased binding affinity to their target peptides. The combined effect of these two mechanisms resulted in improved in vitro activity of two to three orders of magnitude over vancomycin and no propensity to trigger drug resistance in bacteria. In murine model of kidney infection, the optimized compound was able to bring bacterial burden down by about 6 logs at 12 mg kg?1 with no observed toxicity. The results furnished in this report emphasize the potential of this class of compounds as future antibiotics for drug‐resistant Gram‐positive infections. 相似文献
144.
Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering
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Dr. Urška Lešnik Dr. Tadeja Lukežič Dr. Ajda Podgoršek Dr. Jaka Horvat Dr. Tomaž Polak Dr. Martin Šala Branko Jenko Dr. Kirsten Harmrolfs Dr. Alain Ocampo‐Sosa Prof. Dr. Luis Martínez‐Martínez Dr. Paul R. Herron Dr. Štefan Fujs Dr. Gregor Kosec Prof. Dr. Iain S. Hunter Prof. Dr. Rolf Müller Prof. Dr. Hrvoje Petković 《Angewandte Chemie (International ed. in English)》2015,54(13):3937-3940
Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad‐spectrum antibiotic lead was generated with significantly improved activity, including against all Gram‐negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering. 相似文献
145.
Total Synthesis and Biological Evaluation of the Antibiotic Lysocin E and Its Enantiomeric,Epimeric, and N‐Demethylated Analogues
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Dr. Motoki Murai Takuya Kaji Dr. Takefumi Kuranaga Dr. Hiroshi Hamamoto Prof. Dr. Kazuhisa Sekimizu Prof. Dr. Masayuki Inoue 《Angewandte Chemie (International ed. in English)》2015,54(5):1556-1560
Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid‐phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N‐demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action. 相似文献
146.
Zhe Jiao Zongning Guo Suling Zhang Hongwei Chen 《International journal of environmental analytical chemistry》2015,95(1):82-91
In this study, a novel solid-liquid-solid extraction approach, which was termed ‘microwave-assisted micro-solid-phase extraction’ (MAE-μ-SPE), was developed. Target analytes were extracted from the sample into extraction solvent enhanced by microwave field, following adsorption by the adsorbent in the micro-solid-phase extraction device. Without any clean-up steps, the extracts were analysed by high performance liquid chromatography coupled with ultra-violet detector. The MAE-μ-SPE approach was developed for the extraction of four tetracycline antibiotics residues in environmental soil, sludge and atmospheric particulate matters. Variables affecting extraction procedures were systematically investigated. Low detection limits of 0.1–6.3 ng/g and low quantification limits of 0.33–20.7 ng/g were achieved under optimised conditions. The recoveries of antibiotics ranged from 70.6% to 110.5% with relative standard deviation of less than 15.1%. The predominance was showed when compared to conventional MAE and μ-SPE method. According to the results, MAE-μ-SPE was proved to be a simple and effective sample preparation method for the analysis of trace organic contaminants in environmental samples. 相似文献
147.
Structural and Functional Implications of the Interaction between Macrolide Antibiotics and Bile Acids
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Simon Glanzer Sergio A. Pulido Sarah Tutz Dr. Gabriel E. Wagner Dr. Manfred Kriechbaum Nina Gubensäk Jovana Trifunovic Markus Dorn Prof. Dr. Walter M. F. Fabian Prof. Predrag Novak Prof. Dr. Joachim Reidl Prof. Dr. Klaus Zangger 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(11):4350-4358
Macrolide antibiotics, such as azithromycin and erythromycin, are in widespread use for the treatment of bacterial infections. Macrolides are taken up and excreted mainly by bile. Additionally, they have been implicated in biliary system diseases and to modify the excretion of other drugs through bile. Despite mounting evidence for the interplay between macrolide antibiotics and bile acids, the molecular details of this interaction remain unknown. Herein, we show by NMR measurements that macrolides directly bind to bile acid micelles. The topology of this interaction has been determined by solvent paramagnetic relaxation enhancements (solvent PREs). The macrolides were found to be bound close to the surface of the micelle. Increasing hydrophobicity of both the macrolide and the bile acid strengthen this interaction. Both bile acid and macrolide molecules show similar solvent PREs across their whole structures, indicating that there are no preferred orientations of them in the bile micelle aggregates. The binding to bile aggregates does not impede macrolide antibiotics from targeting bacteria. In fact, the toxicity of azithromycin towards enterotoxic E. coli (ETEC) is even slightly increased in the presence of bile, as was shown by effective concentration (EC50) values. 相似文献
148.
对比了3种固相萃取柱(HLB柱、C18柱和PEP柱)对复杂乳品基质中目标物检测的影响,并建立了同时测定乳品中四环素类、β-内酰胺类及氯霉素等8种抗生素残留的固相萃取/高效液相色谱法。结果表明:HLB固相萃取柱的洗脱及净化效果较好,适用于复杂乳品基质的洗脱净化。在优化条件下,8种抗生素在5.0~100.0μg/L浓度范围内的线性关系良好(r20.999),检出限为0.09~0.84μg/kg,定量下限为0.32~2.23μg/kg。8种抗生素在不同加标浓度下(5,10,30μg/kg)的回收率为73.2%~93.3%,相对标准偏差(n=5)为1.4%~3.6%。研究结果表明,该方法适用于复杂乳品基质中8种不同种类抗生素的同时检测。 相似文献
149.
Development and validation of polymerized high internal phase emulsion monoliths coupled with HPLC and fluorescence detection for the determination of trace tetracycline antibiotics in environmental water samples
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Fuyou Du Xian Zheng Lin Sun Qun Qin Lin Guo Guihua Ruan 《Journal of separation science》2015,38(21):3774-3780
A polymerized high internal phase emulsion monolith was used as a novel sorbent for solid‐phase extraction coupled with high‐performance liquid chromatography and fluorescence detection for the determination of oxytetracycline, tetracycline, doxycycline, and chlorotetracycline in environmental water samples. The polymerized high internal phase emulsion monolithic column was prepared by the in situ polymerization of the continuous phase of a high internal phase emulsion containing glycidyl methacrylate, styrene, and divinylbenzene in pipette tips, and then functionalized with iminodiacetic acid. The resulting monolith exhibited highly interconnected porosity and large surface areas, making it an excellent candidate as an solid‐phase extraction sorbent for the enrichment of trace tetracycline antibiotics. Several factors affecting the extraction performance of polymerized high internal phase emulsion monoliths, including the pH of sample solution, the eluting solvents, the sample loading flow rate and volume, were investigated, respectively. Under the optimized conditions, the mean recoveries of oxytetracycline, tetracycline, doxycycline, and chlorotetracycline spiked in pond and farm wastewater samples ranged from 78.1 to 119.3% with relative standard deviation less than 15%. The detection limits (S/N = 3) of the proposed method were in the range of 51–137 pg/mL. This study demonstrated that the monolithic polymerized high internal phase emulsion would be promising solid‐phase extraction sorbents in the extraction and proconcentration of trace analytes from complex samples. 相似文献
150.
建立固相萃取–高效液相色谱法测定地表水中磺胺嘧啶、磺胺二甲嘧啶、磺胺氯哒嗪、醋磺胺甲恶唑4种磺胺类抗生素。样品采用HLB柱进行萃取富集,流动相为甲醇–水(体积比为20∶80),流量为0.5 m L/min,用SPD检测器检测,检测波长为270 nm;采用外标法定量。4种磺胺类抗生素质量浓度在4~160 ng/L范围内与色谱峰面积的线性关系良好,相关系数不低于0.998 2,方法检出限为1.0~1.7 ng/L,样品加标回收率为75.2%~97.4%,测定结果的相对标准偏差为2.8%~6.1%(n=7)。该方法操作简便,灵敏度高,可用于地表水中磺胺类抗生素的检测。 相似文献