一种新的糖肽类抗生素雷莫拉宁研究进展

雷莫拉宁（Ramoplanin、A16686、MDL62，198）是一种新型的糖肽类抗生素，主要抑制革兰氏阳性菌的生长。其纯品是由A1、A2、A3三个组分组成的混合物，其中A2为主要成分，占80％。雷莫拉宁能够特异而迅速地抑制革兰氏阳性菌细菌壁的生物合成。这种抑制作用与万古霉素（Vancomycin)和替考拉宁（Teicoplanin)的抑菌机制不同。体外试验表明，雷莫拉宁对葡萄球菌的抑菌率是万古霉素和替考拉宁的4－8倍，而对链球菌、肠球菌、棒状杆菌、梭菌等多种革兰氏阳性菌都有很强的抑菌活性。另外，雷莫拉宁对许多具有耐药性的病原菌有很好的抑菌效果。雷莫拉宁的细胞毒性较小且无交叉耐药问题。但因其分子量较大，故胃肠道难于吸收，目前，雷莫拉宁主要开发为外用药物。雷莫拉宁在治疗痤疮、感染性外伤以及腹泻感染等病症上已取得了良好的效果，并且已进入了临床试验。     

具有糖基转移抑制活性的抗生素研究进展

细菌细胞壁的骨架肽聚糖的生物合成过程在抗生素治疗中具有重要地位.随着细菌耐药性日益严重,糖基转移过程成为新型抗生素极有潜力的靶标.近年来,糖基转移酶的三维结构的确定,酶与抑制剂复合物结构及其相互作用的详细阐述,都为筛选和研究抑制糖基转移活性的新型抗生素提供了新的突破点.文中依照作用机制的不同,依次论述了直接抑制糖基转移酶活性的抗生素--默诺霉素及其类似物、万古霉素疏水衍生物,和作用于底物脂Ⅱ的抗生素--万古霉素和替考拉宁、雷莫拉宁、硫醚抗生素及一些推测的底物结合物,就其近年的研究进展做一综述.     

雷莫拉宁抗菌机制的研究进展

一直以来,新型抗生素雷莫拉宁的抗菌作用机制存在争议.近期研究表明,雷莫拉宁主要通过结合转糖基酶的作用底物Lipid Ⅱ,使细菌细胞壁合成受阻并致细胞凋亡.本文主要综述其抗菌机制的研究进展.     

雷莫拉宁的研究进展

新型糖肽类抗生素雷莫拉宁(ramoplanin)由游动放线茵(Actinoplanes sp.)发酵液分离获得,其与现有糖肽类抗生素万古霉素和替考拉宁的抑菌机制不同,且对多种耐药致病菌具有很好的抑菌效果,尚未见交叉耐药问题.目前主要开发用于G 菌及其耐药茵引起的皮肤感染及痢疾等胃肠道炎性疾病的治疗.     

恩拉霉素的最新研究进展

本文从恩拉霉素的抗菌活性,在动物生产中的应用研究,检测方法和分离纯化方法的研究,生产工艺的研究,国内外市场现状五个方面综述了恩拉霉素的最新研究进展,并对恩拉霉素未来的研究方向及研究重点进行了展望.旨在为恩拉霉素的生产和应用等方面的研究提供参考和借鉴.     

雷莫拉宁高产菌株的选育

以雷莫拉宁产生菌RM05-55为出发菌株,首先采用紫外诱变复合链霉素抗性筛选,然后进行微波诱变,获得一株雷莫拉宁高产菌株W07-28,其发酵单位较出发菌株提高了59.3%.传代试验表明该菌株的发酵水平较稳定.     

雷帕霉素生物合成基因簇的研究进展

雷帕霉素有效的免疫抑制作用备受关注,尤其是雷帕霉素产生菌吸水链霉菌的雷帕霉素生物合成基因簇的测定,雷帕霉素的生物合成途径得到全面系统的研究.本文从雷帕霉素基因簇出发,重点综述雷帕霉素生物合成代谢的研究进展.     

制备液相色谱法分离纯化恩拉霉素预混剂中恩拉霉素A和恩拉霉素B

目的建立从恩拉霉素预混剂中分离纯化恩拉霉素A和恩拉霉素B的制备高效液相色谱(Pre-HPLC)方法。方法采用正丁醇与酸水反复萃取,利用Pre-HPLC方法对恩拉霉素精制品中的恩拉霉素A和恩拉霉素B进行分离纯化。结果用紫外、质谱和核磁共振法进行结构确证,经分析型HPLC检查,恩拉霉素A和恩拉霉素B的纯度均达98.0%以上。结论由该法制备恩拉霉素A和恩拉霉素B简便、快速,所得产物纯度高,适合于其对照品的制备。     

糖肽类抗生素和链阳性菌素

多肽类抗生素是-类具有复杂结构的高分子多肽化合物,过去临床应用的约有50多种,主要分为下列5类:(1)抗革兰阳性球菌的肽,包括短杆菌肽、杆菌肽等.(2)抗革兰阴性菌的肽,包括多粘菌素B、多粘菌素E等.(3)抗结核杆菌的肽,包括恩维霉素、紫霉素、卷曲霉素等.(4)抗MRSA的糖肽,包括万古霉素、去甲万古霉素、替考拉宁等.(5)具有免疫调节作用的肽,包括环孢素等.……     

雷帕霉素及其衍生物开发现状、作用机制及生物合成研究进展

目的 介绍了近年来雷帕霉素及其衍生物的开发现状、作用机制与生物合成途径,探讨了通过前体定向生物合成与诱变生物合成的方式,获得雷帕霉素衍生物的研究进展,展望了雷帕霉素及衍生物的研究前景.方法 分析、归纳、总结近年来发表的相关文献.结果与结论 雷帕霉素及其衍生物是新型强效的免疫抑制剂与抗肿瘤药物,具有抗真菌、抗增殖及潜在延长哺乳动物寿命周期等作用.采用前体定向生物合成、诱变生物合成与组合生物合成的方式,可快速获得其具药理活性的衍生物.基于生物合成途径,采用系统生物学相关手段可获高产工程化菌种应用于工业化生产.     

Discovery,gene modification,and optimization of fermentation of an enduracidin-producing strain

Abstract

Enduracidin significantly inhibits Gram-positive bacteria and had been widely used in many fields. However, as the poor technology for production of enduracidin and its scarcity, identification of novel strategies for production of enduracidin is important. Our group developed two methods to improve the yield of the production of enduracidin. The yield of enduracidin was increased by three- to fivefold. The highest yields of enduracidin A and enduracidin B achieved were 63.7 and 82.13 mg/ml. Thus, our results might provide a new reference method for the industrial production of enduracidin.     

The in vitro activity of ramoplanin (A-16686/MDL 62,198), vancomycin and teicoplanin against methicillin-susceptible and methicillin-resistant Staphylococcus spp

Ramoplanin (A-16686/MDL 62,198) is a novel lipoglycopeptide antimicrobial, comprised of three closely related polypeptides containing chlorinated phenyl moieties and D-mannose, isolated from the fermentation products of Actinoplanes sp. ATCC 33076. The antimicrobial activity of ramoplanin is limited to Gram-positive bacteria and its reportedly unacceptable administration side-effects suggest that any potential clinical role will be limited to the topical therapy of superficial skin infections and the eradication of bacteria, representing a possible nosocomial cross-infection source, from carriage sites. In this study the MICs of ramoplanin have been determined for methicillin-susceptible and methicillin-resistant isolates of Staphylococcus aureus, S. epidermidis and S. haemolyticus and compared with those of two glycopeptide antimicrobials, vancomycin and teicoplanin. MICs were determined using an agar incorporation technique in Mueller-Hinton medium with an inoculum of 10(5) cfu. Ramoplanin was 2-8 times more active than either vancomycin or teicoplanin against methicillin-susceptible and methicillin-resistant isolates of S. aureus and methicillin-susceptible isolates of S. epidermidis. Isolates of methicillin-resistant S. epidermidis and both methicillin-susceptible and -resistant isolates of S. haemolyticus were generally less susceptible to teicoplanin than to vancomycin. Ramoplanin was significantly more active than either vancomycin or teicoplanin against these isolates. These results suggest that the clinical evaluation of ramoplanin as a topical antibacterial agent for the control of superficial infections caused by Staphylococcus spp. and for the eradication of methicillin-resistant S. aureus from carriage sites, is justified.     

Synthesis and preliminary biological characterization of new semisynthetic derivatives of ramoplanin

Ramoplanin is a glycolipodepsipeptide antibiotic active against Gram-positive bacteria including vancomycin-resistant enterococci. Ramoplanin inhibits bacterial cell wall biosynthesis by a mechanism different from that of glycopeptides and hence does not show cross-resistance with these antibiotics. The systemic use of ramoplanin has been so far prevented because of its low local tolerability when injected intravenously. To overcome this problem, the fatty acid side chain of ramoplanin was selectively removed and replaced with a variety of different carboxylic acids. Many of the new ramoplanin derivatives showed antimicrobial activity similar to that of the natural precursor coupled with a significantly improved local tolerability. Among them the derivative in which the 2-methylphenylacetic acid has replaced the di-unsaturated fatty acid side chain (48) was selected as the most interesting compound and submitted to further in vitro and in vivo characterization studies.     

Syntheses, in vitro antibacterial and cytotoxic activities of a series of 3-substituted succinimides

We have synthesized a series of 3-substituted succinimides and their in vitro antibacterial activities have been tested towards Gram-positive and Gram-negative bacteria from the ATCC collection. Some of them possess significant antibacterial activity against Gram-positive organisms (Staphylococcus aureus ATCC 25923 and Enterococcus faecalis ATCC 29212) but all are poorly active or inactive against Gram-negative organisms (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853). The compounds with the lowest minimal inhibitory concentrations (esters of 3-hydroxy succinimides) are also the most cytotoxic against green monkey Vero cell line (ATCC CCL-81) and could explain that perhaps apoptosis should be implicated in eukaryotic cell cytotoxicity of succinimides.     

Ramoplanin (A-16686), a new glycolipodepsipeptide antibiotic. III. Structure elucidation

By combination of chemical, 1H and 13C NMR, and mass spectrometric studies, the structures of the three components of the antibiotic ramoplanin (A-16686), produced by Actinoplanes sp. ATCC 33076, have been elucidated. All the components have structures formed by a common depsipeptide skeleton carrying a dimannosyl group and are differentiated by the presence of various acylamide moieties, derived from C8, C9 and C10 fatty acids.     

新糖脂类化合物抗革兰阳性球菌作用机制研究

目的研究新糖脂化合物二鼠李糖脂衍生化合物7(DDC7)和鼠李糖脂(C5)抗革兰阳性球菌的作用机制。方法分离纯化金黄色葡萄球菌(ATCC29213)的细胞壁肽聚糖。依据已知新化合物对ATCC29213的MIC结果,用肉汤二倍稀释法,观察新化合物DDC7、C5分别加入不同浓度肽聚糖后,对ATCC29213生长的影响。结果新化合物DDC7、C5对ATCC29213的MIC均为16μg·mL-1。当加入肽聚糖浓度≥32μg·mL-1时,可以阻断新化合物DDC7、C5对ATCC29213的抑菌作用。结论新糖脂类化合物抗菌作用部位在革兰阳性球菌细胞壁肽聚糖上。     

Glycopeptides and glycodepsipeptides in clinical development: a comparative review of their antibacterial spectrum, pharmacokinetics and clinical efficacy

Hemi-synthetic derivatives of glycopeptides have demonstrated bactericidal activity towards Gram-positive bacteria, including vancomycin-resistant strains (oritavancin and telavancin), and a prolonged half-life, allowing for once-daily (oritavancin and telavancin) or once-weekly (dalbavancin) administration. These compounds have proved effective for the treatment of infections caused by multidrug-resistant Gram-positive bacteria, including complicated skin and skin structure infections (oritavancin, telavancin and dalbavancin), bacteremia (oritavancin and dalbavancin) and nosocomial pneumonia. This review compares the antibacterial activity and clinical activity of three glycopeptides, oritavancin, telavancin and dalbavancin, and the natural lipoglycopeptide, ramoplanin, which, being unstable in the bloodstream, is administered orally to treat Clostridium difficile colitis and for digestive tract decontamination. All of these compounds, with the exception of oritavancin, have received Fast Track designation from the FDA because of their clinical efficacy.     

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.     

Antibacterial and antifungal activities of complexes of ruthenium (II).

Twenty ruthenium (II) complexes (1-5) were evaluated for their in vitro antibacterial and antifungal activity against Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Candida albicans and Candida tropicalis. Compounds 1d, 1e, 1h, 1i and 1j showed more pronounced antimicrobial activity against Gram-positive bacteria and fungi as compared to the nitrogen donor ruthenium complexes; hydrophobic substituents were significantly more effective. None of the compounds 1-5 exhibited antimicrobial activity against the Gram-negative strains Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 27853) with the concentrations ranging between 12.5 and 800 micrograms/ml.     

Synthesis and antibacterial activity of 4-benzoyl-1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid and derivatives

Some new 1H-pyrazole-3-carboxylic acid and pyridazinone derivatives were synthesized and evaluated for their antibacterial activities against Bacillus cereus ATCC 7064, Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 4230 and Pseudomonas putida using tube dilution method. The minimal inhibitory concentrations (MICs) experiments revealed that all chemical compounds showed inhibitor effects on the growth of the test microorganisms. Moreover, the results of this research showed that the compound named as 5c was the best compound in the series, exhibiting antibacterial activity against both Gram-positive and Gram-negative bacteria.