万古霉素类糖肽抗生素的构效关系

本文论述了万古霉素类糖肽抗生素的构数关系。对天然存在的万古霉素类抗生素，讨论了核心六元肽的氨基酸，１，２，３，４，６上进行化学修饰后的构效关系；系统研究了半合成糖肽抗生素的Ｎ－酰基，Ｎ－烷基衍生物的构效关系。结果表明，Ｎ－烷基糖肽类抗生素不仅抗Ｇ＾＋菌的活性比万古霉素大５倍，而且对耐万古霉素的肠球菌有效。     

糖肽类抗生素的抗菌作用机理

糖肽类抗生素产生菌、抗菌谱及主要用途 糖肽类抗生素和万古霉素类抗生素,系两性高分子碳水化合物,有相近的化学结构,由放线菌、诺卡氏菌、链霉菌、游动放线菌及Kibdelosporangium等(见表一)产生。除万古霉素、利托菌素、Teicoplanin在临床上有所应用外,其它大多用作饲料添加剂。 万古霉素主要适用于耐青霉素的金葡菌所致各种感染,如败血症、肺炎、心内膜炎等。对林可霉素所致结肠炎有特效。万古霉素不易产生耐药性,与其他抗生素无交叉耐药。肌注易引起局部反应和组织坏死,仅限于静注或滴注。过敏反应有嗜曙红细胞增多、荨麻疹,药热较为常见,亦有肾毒性和听力损     

血液病患者54例去甲万古霉素治疗后尿特种蛋白检测分析

去甲万古霉素为糖肽类抗生素，对革兰阳性菌有强大杀菌力。临床主要用于耐甲氧西林的金黄色葡萄球菌、表皮葡萄球菌和肠球菌引起的严重感染的治疗。但其肾毒性使该药的临床应用受到一定影响。本文观察了54例血液病患者粒细胞缺乏时继发感染的病例，应用去甲万古霉素治疗后的临床特点，探讨尿特种蛋白与肾毒性的关系。     

ESI和质谱阐明新型抗MRSA抗生素中小组分WAP-8294A II结构特性

由耐甲氧西林金黄色葡萄球菌(MRSA)引起的院内感染仍然是很严重的临床问题,在治疗MRSA引起的感染时,常用的抗生素有:糖肽类抗生素(万古霉素、替考拉宁),氨基糖苷类抗生素(阿贝卡星arbekacin).     

糖肽类抗生素雷莫拉宁(Ramoplanin)的研究进展

20世纪80年代以来，革兰阳性菌在医院感染中的比例显著上升，其耐药性也日趋严重和复杂。多重耐药性问题成为人类面临的严峻挑战之一。糖肽类抗生素是治疗耐甲氧西林金黄色葡萄球菌（金葡球菌，MRSA）的首选药物。自1959年万古霉素用于临床以来，它一直是治疗革兰阳性菌引起的严重感染的最有效的药物之一。绝大多数引起临床感染的革兰阳性菌，均对万古霉素敏感。但随着万古霉素广泛使用，以及临床用药中的不合理现象，导致了耐药问题逐渐发生并有流行的可能。1986年，首先在英国报道耐万古霉素肠球菌（VRE）后，世界各地均有VRE发生。不仅如此，1996年在日本发现了第一株糖肽类抗生素中度敏感的金黄色葡萄球菌（中敏金葡菌，GISA），随后在法国、美国、英国等地又陆续发现多株。国外由GISA引起的感染已有10多例报道，且有蔓延的趋势。[第一段]     

糖肽类抗生素的作用机制及肠球菌的糖肽耐药机制

糖肽类抗生素通过与细菌细胞壁以D－Ala-D-Ala为末端的肽聚糖前体小肽特异性结合,抑制细菌细胞壁肽聚糖的延伸或／和交联,从而阻遏细胞壁的合成,最终导致细菌细胞死亡。糖肽类抗生素对几科所有的革兰氏阳性菌具有活性,在临床上用于严重的革兰氏阳性菌感染的治疗,代表着对付这类难治性疾病的最后防线,随着20世纪80年代万古霉素耐药耐肠球菌的出现。糖肽耐药性肠球菌不断增多,近期甚至出现了糖肽耐药基因从肠球菌向其它细菌转移的现象,由于尚缺乏有效治疗糖肽耐药菌感染的药物,糖肽耐药性已成为威胁人类生存和健康的一大难题。从已有的研究发现,肠球菌的糖肽耐药表现型有5种,即VanA、VanB、VanC、VanD和VanE型,前2种较多见,为诱导性耐药表型,VanA型菌株对万古霉素和替考拉宁都具有高水平耐药性,VanB型菌株对万古霉素具有水平各异的耐药性且保持对替考拉宁的和敏感性。     

ESISN质谱阐明新型抗MRSA抗生素中小组分WAP-8294AⅡ结构特性

由耐甲氧西林金黄色葡萄球菌（MRSA）引起的院内感染仍然是很严重的临床问题,在治疗MRSA引起的感染时,常用的抗生素有：糖肽类抗生素（万古霉素、替考拉宁）,     

糖肽类抗生素发展动态综述

20世纪80年代以来，革兰阳性菌在医院感染中的比例显著上升，其耐药性也日趋严重和复杂．多重耐药性问题成为人类面临的严峻挑战之一。糖肽类抗生素是治疗耐甲氧西林金黄色葡萄球菌（金葡球菌，MRSA）的首选药物。自1959年万古霉素用于临床以来．它一直是治疗革兰阳性菌引起的严重感染的最有效的药物之一。绝大多数引起临床感染的革兰阳性菌，均对万古霉素敏感。     

成人万古霉素血药浓度监测的探讨

万古霉素(糖肽类抗生素)是治疗耐甲氧西林金黄色葡萄球菌(MRSA)感染的主要药物之一。进行血药浓度监测,能降低毒性和提高疗效。AUC/MIC是预测万古霉素疗效的重要参数,监测谷浓度是最为准确和实用的方法;但并非所有患者都必须进行监测。应继续开展相关研究,促进万古霉素临床使用安全、有效。     

Eremomycin的氨甲基化修饰及衍生物的抗菌活性

dalbaheptide型糖肽类抗生素(万古霉素和替考拉宁)已广泛用于治疗由甲氧西林耐药性葡萄球菌和凝固酶阴性葡萄球菌(CNS)引起的感染,还用于治疗多重耐药性肠球菌感染.万古霉素和替考拉宁代表了治疗这些难治性病原菌感染的最后防线.最近发现在VanA肠球菌中出现糖肽类抗生素耐药性,一些CNS菌株对替考拉宁,偶尔对万古霉素的敏感性已有所减弱,这给未来的治疗造成严重的威胁,迫切需要新的更强的糖肽类抗生素,即对多重耐药性葡萄球菌活性更高、对糖肽类抗生素高耐药性VanA肠球菌有活性的抗生素.     

Polycyclic peptide and glycopeptide antibiotics and their derivatives as inhibitors of HIV entry

Antiviral activity and other biological properties of two groups of polycyclic peptides are discussed. Antibiotics of the complestatin-kistamycin group have a structural motif similar to that of the peptide core of antibacterial antibiotics of the vancomycin-teicoplanin group though no amino acid component in the chloropeptin-kistamicin antibiotics is identical to an amino acid incorporated in the peptide core of the antibiotics of the vancomycin-teicoplanin group. Chloropeptins and the hydrophobic several derivatives of antibacterial antibiotics are inhibitors of HIV and some other viruses. They interfere with the viral (i.e. HIV) entry process. Chemical modifications of natural glycopeptide antibiotics led to the compounds with antiviral properties whereas antibacterial properties were lost. These glycopeptide aglycons derivatives can be envisaged as potential lead compounds for application as microbicides against sexual HIV transmission.     

细菌对MLS类和糖肽类抗生素产生耐药性的作用机制

MLS类和糖肽类抗生素在人类与细菌感染性疾病的对抗中发挥着重要作用.与其他抗生素一样,随着这些抗生素的临床使用,细菌耐药性的出现和不断发展给人们带来新的挑战.本综述对这两类抗生素的细菌耐药性产生机制进行了剖析,并就已开发的若干个新型MLS类和糖肽类抗生素作了介绍.     

Semisynthetic derivatives of mannopeptimycin antibiotics active against multi-drug resistant Gram-positive bacteria

The incidence of hospital infections due to Gram-positive bacteria is continuously increasing. Most of these organisms have become resistant to first-line antibacterial agents and they pose a serious clinical problem as current therapeutic options are limited. It follows an urgent need for new agents, possibly provided with novel mechanisms of action, that prove to be effective against multi-drug resistant Gram-positive pathogens, particularly methicillin-resistant staphylococci, including strains of Staphylococcus aureus with reduced susceptibility to glycopeptides, penicillin-resistant pneumococci and vancomycin-resistant enterococci. In this patent, American Cyanamide Co. presents a new class of glycopeptide derivatives of the natural products mannopeptimycins, which do not belong to the vancomycin family, that show interesting activity against most of the above resistant Gram-positive bacteria. Some of these compounds are worthy of further development to be considered as a possible alternative to other innovative antibiotics that have been launched into the market recently or are currently undergoing clinical development.     

Inhibition of feline (FIPV) and human (SARS) coronavirus by semisynthetic derivatives of glycopeptide antibiotics

Various semisynthetic derivatives of glycopeptide antibiotics including vancomycin, eremomycin, teicoplanin, ristocetin A and DA-40926 have been evaluated for their inhibitory activity against feline infectious peritonitis virus (FIPV) and human (SARS-CoV, Frankfurt-1 strain) coronavirus in cell culture in comparison with their activity against human immunodeficiency virus (HIV). Several glycopeptide derivatives modified with hydrophobic substituents showed selective antiviral activity. For the most active compounds, the 50% effective concentrations (EC(50)) were in the lower micromolar range. In general, removal of the carbohydrate parts of the molecules did not affect the antiviral activity of the compounds. Some compounds showed inhibitory activity against both, whereas other compounds proved inhibitory to either, FIPV or SARS-CoV. There was no close correlation between the EC(50) values of the glycopeptide derivatives for FIPV or SARS-CoV.     

Synthesis and biological evaluation of de(acetylglucosaminyl)didehydrodeoxy derivatives of teicoplanin antibodies

A series of 34-de(acetylglucosaminyl)-34-deoxy derivatives of 34,35- and 35,52-didehydro teicoplanin antibiotics have been synthesized from teicoplanin and its N-acetylglucosamine containing pseudoaglycons under basic conditions. The structures of these compounds have been determined by 1H NMR, UV, and FAB-MS. 35,52-Unsaturated derivatives maintained in vitro and in vivo antimicrobial activity to a different extent as well as the ability for binding to Ac2-L-Lys-D-Ala-D-Ala, a bacterial cell-wall model for the site of action of glycopeptide antibiotics. In contrast, 34,35-unsaturated compounds were markedly less active and possessed a negligible affinity for the synthetic tripeptide.     

支链氨基酸代谢在糖肽类和环脂肽类抗生素产量提高与组分优化中的应用

摘要：糖肽类和环脂肽类抗生素具有很好的抗菌活性,临床上广泛用于治疗多重耐药菌导致的严重感染。大部分糖肽类和 环脂肽类抗生素均含有带支链结构的脂肪酸侧链,侧链结构差异是导致这两类抗生素发酵组分多样性的主要原因。支链脂肪酸 侧链的合成起始于支链氨基酸分解代谢,调控支链氨基酸代谢对于定向合成含有特定脂肪酸侧链的糖肽类和环脂肽类抗生素具 有重要作用。本文从糖肽类和环脂肽类抗生素中脂肪酸侧链的生源途径、外源添加支链氨基酸对糖肽类和环脂肽类抗生素产量 和组分的影响,内部改造支链氨基酸代谢途径对糖肽类和环脂肪肽类抗生素产量和组分的影响3方面进行了综述。     

Section Review Anti-infectives: New approaches to the treatment of vancomycin-resistant bacterial infections

Commercially available glycopeptides Vancomycin (V) and Teicoplanin (T) are drugs of choice for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (CNS), which are resistant to beta-lactams and almost all other first-line antibiotics. They are extensively used in the treatment of severe infections caused by multi-resistant Gram-positive pathogens including enterococci. Enterococcal infections have become a dramatic clinical problem since few antibacterial agents are efficacious against these refractory organisms and increasing resistance is rapidly eliminating the current options. The recent emergence and spread of resistance also to glycopeptides in VanA enterococci poses a serious threat for the future. Some strains of methicillin-resistant CNS have reduced susceptibility to T and occasionally to V. Currently, a major concern is the possibility already demonstrated at laboratory level, that high glycopeptide resistance could be transferred from enterococci to staphylococci. It follows that there is an urgent need for new more potent glycopeptides which combine improved activity against methicillin-resistant staphylococci with excellent activity against highly glycopeptide-resistant enterococci (GRE), or alternative drugs effective against these multi-resistant bacteria. This article describes the most recent findings and results achieved in this field with new glycopeptide derivatives and novel approaches based on modifications of the natural glycopeptide-core structure. Other promising investigational drugs potentially useful for overcoming the serious therapeutic problem of glycopeptide-resistant bacterial infections are also reviewed.     

Role of the glycopeptide framework in the antibacterial activity of hydrophobic derivatives of glycopeptide antibiotics

The antibacterial properties of glycopeptide antibiotics are based on their interaction with the d-Ala-d-Ala containing pentapeptide of bacterial peptidoglycan. The hydrophobic amides of vancomycin (1), teicoplanin (2), teicoplanin aglycon (3), and eremomycin (4) were compared with similar amides of minimally or low active des-(N-methyl-d-leucyl)eremomycin (5), eremomycin aglycon (6), des-(N-methyl-d-leucyl)eremomycin aglycon (7), and a teicoplanin degradation product TB-TPA (8). All hydrophobic amides of 1, 3, 4, and 6 were almost equally active against glycopeptide-resistant enterococci (GRE) [minimum inhibitory concentrations (MIC) 相似文献   

Recent developments in glycopeptide antibacterials

The glycopeptide class of antibiotics, namely vancomycin and teicoplanin, are intravenously administered in the hospital setting for the treatment of the most severe of Gram-positive infections. Although a mainstay of the hospital formulary for over four decades, the rise of increasingly frequent high-level vancomycin resistance in enterococci and low-level resistance in staphylococci (as well as a few high-level vancomycin resistance cases) has highlighted the need for the identification of naturally occurring and semi-synthetically modified glycopeptide derivatives that have antibacterial activity against these resistant strains. Among the leading development candidates are dalbavancin, oritavancin, telavancin and ramoplanin, each of which provides a unique microbiological and pharmacological profile to fill an important unmet medical need.     

N-alkyl-substituted glycopeptide antibiotics

The glycopeptide antibiotic vancomycin has proved valuable in the treatment of staphylococcal and enterococcal infections, particularly those caused by strains resistant to other antibiotics. The emergence of high-level resistance to vancomycin within the enterococci, and its potential for transfer to other pathogenic Gram-positive cocci, has led to interest in developing new glycopeptide antibiotics with activity against vancomycin resistant organisms. The N-alkylated glycopeptide antibiotics, under development by Lilly Research Laboratories, represent a new series of compounds possessing these properties. The lead compound in this series, LY 333328, is reported to be in Phase I trials.