抗生素糖基转移酶研究进展

糖苷类抗生素是临床上广泛应用的抗菌和抗肿瘤化合物。该类化合物在体内由糖基转移酶催化，糖基化反应通常在抗生素生物合成的最后发生，糖基的位置、类型和数量对糖苷类抗生素的活性有很大的影响。本文综述了糖基转移酶的种类、功能、特性及其在组合生物合成中的应用与研究前景。     

抗绿脓杆菌的β-内酰胺类抗生素

绿脓杆菌感染,尤其当该菌耐氨基糖苷类抗生素时是难治的;而广泛用以治疗绿脓杆菌感染的羧苄青霉素及羧噻吩青霉素(Ticarcillin)对该菌仅具中等抗菌活性。本文讨论近年来发展的具有较强抗绿脓杆菌活性的β-内酰胺类抗生素,其中包括新的头孢菌素类、青霉素类、恶唑β-内酰胺类、硫霉素(Thienamycin)及诺卡菌素A(Nocardicin A)。对这些药物的评价要考虑到多种因素。β-内酰胺类抗生素的抗绿脓杆菌活性决定于其穿透细胞壁的能力和在细胞膜上与青霉素结合蛋白的亲和力,同样重要的是它对β-内酰胺酶的稳定性;并须结     

当前肺部感染诊治的难点及对策

１ β 内酰胺类抗生素的抗菌与耐药机制目前临床上常用于抗肺部感染的 β 内酰胺类抗生素主要为青霉素类和头孢菌素两大类。该类药物的有效抗菌活性必须具备如下的一些基本条件 ,即容易穿透细菌的外膜 ;能抵挡住病原菌所产生的β 内酰胺酶 (ＢＬＡ)的水解和灭活 ;并能与细菌细胞膜上的青霉素结合蛋白 (ＰＢＰｓ)结合和相互作用 ,从而发挥抑菌和杀菌的作用。然而 ,近代临床研究表明 ,病原菌对 β内酰胺类抗生素的耐药日益增多 ,该类抗生素的抗感染疗效远不如以前。其耐药机制主要有 :(１)病原菌产生ＢＬＡ ,水解破坏β内酰胺类抗生素的核心结…     

双芳环酰胺类及苯并咪唑类化合物的合成及其抗柯萨奇病毒活性研究

目的设计并合成一系列新的双芳环酰胺类和苯并咪唑类衍生物,对其抗柯萨奇病毒活性进行初步评价。方法考察双芳环中A环上3位和4位取代基、B环上取代基及双芳环间的酰胺链对活性的影响,并采用细胞病变程度(CPE)方法测定了目标化合物对柯萨奇病毒的抑制活性。结果与结论共合成了10个双芳环酰胺类和4个苯并咪唑类化合物,其中,11个目标化合物(1a~1c、2a~2d、3b、4b~4d)未见文献报道,所有目标化合物的结构经1H-NM R和ESI-M S确证。该类化合物抗柯萨奇病毒活性的初步筛选结果显示,多个化合物对柯萨奇病毒B3亚型具有抑制活性,其中化合物1c表现出最强的抑制活性,选择性指数达到106.38。     

一株海兔来源真菌 Aspergillus terreus丁内酯类化合物及其生物活性研究

摘要：目的 在生物活性和化学方法指导下,从1株海兔来源真菌 Aspergillus terreus (RA29-5)中分离鉴定海洋天然产物,并对其进行生物活性评价。方法 运用硅胶柱层析、Sephadex LH-20凝胶柱层析和HPLC等方法分离纯化化合物,利用NMR等现代波谱分析方法,对化合物进行结构鉴定,并对化合物进行抗菌、卤虫致死和斑马鱼胚胎毒性活性评价。结果 鉴定了 9 个丁内酯类化合物 (1～9) 的结构;抗菌活性表明,除化合物 6 和 9 外,所有化合物对四株致病细菌白色葡萄球菌 Staphylococcus epidermidis、金黄色葡萄球菌 Staphylococcus aureus、蜡状芽孢杆菌 Bacillus subtilis 和四联球菌 Tetragenococcus halophilus 都显示一定的抗菌活性;化合物 1～4 和7均对真菌芒果叶枯菌 Pestalotia mangiferae 显示抗菌活性;特别的,化合物 7 对测试的13株致病菌都具有广谱地抗菌活性,其MIC值在1.11~8.88 μmol/L之间;此外,还对化合物的抗菌活性构效关系进行了初步探讨。结论 海兔来源真菌 A. terreus (RA29-5) 可产生结构多样的丁内酯类化合物,该类化合物具有开发成抗菌剂的潜力。     

一株南沙群岛柳珊瑚来源真菌 Aspergillus terreus 中化合物及 mPTPB 酶抑制活性研究

目的 从1株南沙群岛柳珊瑚来源真菌 Aspergillus terreus (NS02-09)中分离鉴定海洋天然产物,对所得化合物进行结核分枝杆菌酪氨酸磷酸激酶 (mPTPB) 抑制活性评价。方法 运用多种色谱手段分离纯化化合物,利用NMR、CD等现代波谱分析方法,对化合物进行结构鉴定、,通过衍生物制备获得两个乙酰化衍生物(2a和2b);并对化合物2及其衍生物2a和2b进行mPTPB酶抑制活性测试。结果 鉴定了1个土曲霉酮(1)和1个丁烯酸内酯 (2) 的结构; 2具有较强的mPTPB酶抑制活性,而其乙酰化产物(2a和2b)的mPTPB 酶抑制活性显著降低。运用Sybyl X 1.3 软件,对2与mPTPB酶的模拟对接计算发现,丁烯酸内酯环及环上的羟基是化合物2发挥酶抑制活性的重要作用基团。结论 从柳珊瑚来源真菌 A. terreus (NS02-09) 中发现了具有mPTPB 酶抑制活性的丁烯酸内酯类化合物,并对其作用机制进行了计算研究,该类化合物的相关研究对抗结核药物先导化合物发现具有借鉴作用。     

碳青霉烯类抗生素的研究概况

碳青霉烯类抗生素具有独特的化学结构和临床应用价值,该类化合物从一出现就显示出良好的抗菌效果及对β-内酰胺酶稳定的特点,引起了研究人员的高度关注和深入研究,至今对该类化合物的研究已取得了很大进展.本文将从碳青霉烯类抗生素的研发史、已上市和尚处于研究阶段的品种、目前研究中面临的问题和研究方向等方面讨论、阐述该类抗生素的研究概况.     

碳青霉烯类抗生素的电喷雾质谱裂解规律分析

目的:研究碳青霉烯类抗生素的质谱(MS)裂解特征,探讨该类化合物的MS裂解规律。方法:正离子检测模式下,利用电喷雾三重四极杆MS对4种碳青霉烯类抗生素(亚胺培南、美罗培南、帕尼培南、比阿培南)的[M+H]+离子,以及由其产生的特征碎片离子进行MS/MS及准MS/MS/MS分析。结果:正离子检测模式下,碳青霉烯类抗生素主要以[M+H]+准分子离子形式存在;其裂解行为是离子[M+H]+主要发生四元环裂解反应、脱羧基反应及碳-硫键的裂解反应,产生相应的特征子离子C、D、G、H。结论:该方法可获得碳青霉烯类抗生素的多级MS信息;依靠MS裂解规律,可以对其类似物、衍生物及代谢物进行快速定性鉴别,并为其定量分析提供有力的理论依据。     

短柔毛大戟中能逆转小鼠淋巴瘸细胞多药耐药性的二萜成分[英]／Valente C…／／Planta Med

作者曾从短柔毛大戟(拟)Euphorbia pubesens Vahl中分得3个假白榄烷型二萜多酯pubescene A(1)、B(2)、C(3)。现又从该植物中分得一新的该类化合物pubescene D(4)并研究了化合物1～4逆转小鼠淋巴瘤细胞多药耐药性(MDR)的活性。     

1,2,3-三氮唑类苦参碱衍生物的合成及其体外抗肿瘤活性研究

目的设计并合成了1,2,3-三氮唑类苦参碱衍生物,并对其进行体外抗肿瘤活性研究。方法以苦参碱为起始原料,通过水解反应、N-烷基化反应、click反应等反应得到目标化合物。采用噻唑蓝(MTT)法考察所合成目标化合物对HeLa、MCF-7和HepG23种肿瘤细胞的体外抗增殖活性。结果合成了9个1,2,3-三氮唑类苦参碱衍生物,其结构经~1H-NMR,~(13)C-NMR及HR-MS确定,抗肿瘤活性测试结果表明该类化合物具有一定的抗肿瘤活性,其中化合物5h对MCF-7肿瘤细胞表现出良好的活性,且活性优于母体化合物苦参碱。结论部分目标化合物具有较好的抗肿瘤活性,为该类抗肿瘤化合物的进一步优化提供思路。     

A new anti-MRSA antibiotic complex, WAP-8294A II. Structure characterization of minor components by ESI LCMS and MS/MS

The anti-MRSA antibiotic, WAP-8294A, was isolated from the fermentation broth of Lysobacter sp. The major component, WAP-8294A2, is composed of 1 mol of Gly, L-Leu, L-Glu, D-Asn, D-Trp, D-threo-β-hydroxyasparagine, N-Me-D-Phe and N-Me-L-Val, and 2?mol of L-Ser, D-Orn and D-3-hydroxy-7-Me-octanoic acid. The structure of the WAP-8294A2 was mainly determined as a cyclic depsipeptide by 2D NMR experiments. However, it was difficult to use the NMR experiment to determine the minor components, A1, A4 and Ax13, isolated in small amounts. In the present study, ESI MS/MS was applied to the structure elucidation of these minor components. The structures of these minor components were determined on the basis of the fragmentation pattern of the product ions of WAP-8294A2 in the ESI MS/MS. As a result, it was confirmed that A1 and A4 had the same amino acid sequence as A2, while A1 and A4 had the 3-OH-octanoic acid and 3-OH-8-Me-nonanoic acid, respectively, in the place of the 3-OH-7-Me-octanoic acid in A2. In the structure of Ax13, it was found that Gly of A2 was changed to β-Ala of Ax13.     

Antibiotic activities of cefuzoname and the representative cephalosporins against clinically isolated methicillin resistant strains of Staphylococcus

Incidences of methicillin-resistant strains of Staphylococcus (MRS) have been increasing because of the extensive uses of cephalosporins and semisynthetic beta-lactamase-resistant penicillins. Most of these strains are known to be resistant to beta-lactam antibiotics due to their production of penicillinases and mutated penicillin-binding proteins. Our recent clinical isolates of MRS were also suspected to be this type because of their temperature sensitive resistance to methicillin. We studied in vitro antibiotic activity of cefuzoname (CZON) a cephalosporin developed against Staphylococcus, against these MRS in comparison with those of the representative cephalosporins, cefazolin (CEZ), cefamandole (CMD), cefotiam (CTM), cefoperazone (CPZ) and cefpiramide (CPM). It was found that CZON was the most active against MRS among these cephalosporins under normal body temperatures as well as at lower temperatures.     

Occurrence and fate of antibiotics in manure during manure treatments: A short review

Veterinary antibiotics are frequently applied in livestock farming worldwide and their usage is expected to increase during the next years by more than 60%. The aim of this review is to give a brief overview about excretion rates reported for diverse antibiotics and their fate within different manure treatments. Depending on the substance, < 5% up to 90% of the active ingredient were found to be excreted by the treated organisms leading to antibiotic residues in animal waste. As manure is utilized as substrate in biogas plants, antibiotics can enter this process and might have an effect on biogas and methane yield. This crucial point was subject of several anaerobic digestion studies giving variable results from increased biogas production in only one case (+ 14%) up to almost complete inhibition (? 93%). The fate of antibiotics such as fluoroquinolones, sulfonamides or tetracyclines during manure treatment (anaerobic digestion, storage, composting) was investigated in different setups with composting often resulting in the highest elimination rates (up to > 99%). Based on reported transformation products of distinct antibiotics, degradation cannot be presumed for most compounds. In many cases, only minor structural modifications were observed and several transformation products are still microbiologically active. Consequently, manure treatments should not be evaluated based on the disappearance of the parent compound only. Comprehensive studies should include the elucidation of elimination pathways to identify efficient processes for reducing the input of antibiotics into the environment.     

烯二炔类抗肿瘤抗生素及其靶向药物研究近况

烯二炔类抗生素是一种结构新颖、作用机制独烯二炔结构是其活性中心。该类抗生素具有极强的抗肿瘤活性却因毒性较大难以直接用于临床。近年来,研究人员展开了烯二炔类抗生素靶向药物的研发工作,以提高其肿瘤靶向性并减少药物毒副作用。归纳总结了已报道的天然来源的烯二炔类抗肿瘤抗生素及其活性代谢物,并重点介绍烯二炔类抗生素相关靶向药物的研究进展,旨在为其深度开发提供参考。     

异源表达策略在抗生素研究中的应用进展

异源表达在抗生素研究中有广泛的应用,如鉴定基因功能、克隆抗生素合成基因、调节基因表达、提高抗生素产量、组合生物合成和发现活性代谢产物等各个方面。本文简单综述异源表达策略在抗生素研究中的应用进展。     

Impact of beta-lactamases on the clinical use of beta-lactam antibiotics

beta-Lactamase production is a very common mechanism of antibiotic resistance, occurring in a wide variety of important pathogens involved in both community-acquired and nosocomial infections. The beta-lactamases can be divided into four classes (A, B, C, and D), each of which contains both chromosomal and plasmid-encoded enzymes. The impact of beta-lactamases on the clinical use of beta-lactam antibiotics depends on the spectrum of activity of the enzymes, the prevalence of beta-lactamase production in a given species, the frequency of involvement of the pathogen in infections, and whether the infection is treated in hospital or in the community. The class A and class C beta-lactamases generally have the most impact on clinical practice. Plasmid-mediated class A enzymes are produced by a wide range of common pathogens; these enzymes are primarily penicillinases such as TEM(1), SHV(1) and ROB(1), but in addition include extended-spectrum beta-lactamases which can also hydrolyze cephalosporins. The vast majority of the class A enzymes can be inhibited by currently-available beta-lactamase inhibitors. The class C enzymes or cephalosporinases, production of which is related to the presence of beta-lactam inducers, are present in nosocomial pathogens such as members of the Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. Constitutive hyperproduction of class C enzymes, resulting from mutations in regulatory genes, leads to third-generation cephalosporin resistance in these organisms. To provide the best antimicrobial treatment, and to ensure that beta-lactam antibiotics are used to their optimum effect, clinicians need to remain aware of the prevalence of particular beta-lactamases in their areas or institutions, and to make use of appropriate counter measures such as beta- lactam beta- lactamase inhibitor combinations.     

Antibiotics threats on vegetables and the perils of low income nations practices

Loose control on antibiotics usage, improper waste disposal, the use of reclaimed water in crop production, and other poor practices can enhance the antibiotic contamination of soil, water and the environment. These then threaten food safety and human health. Highly susceptible crops such as vegetables easily accumulate antibiotics and can be a viable route for the spread of antibiotics resistant bacteria and the induction of antibiotics resistant genes. This paper discusses common usages and negative impacts of antibiotics, and the extent of their contamination in various environmental components viz-a-viz their impact on vegetables. Peculiar challenges and practices related to low income nations (LINs) as well as their consequential effects are also discussed. Areas of future research that needs attention in LINs are succinctly presented. This review therefore will serve as tool to increase the awareness of consumers, food producers, environmentalists and policy makers on the impact of antibiotics and inadequate practices on vegetable production.     

Isolation and characterization of new peptide antibiotics, plusbacins A1-A4 and B1-B4.

New antibiotics, plusbacins A1-A4 and B1-B4, were isolated from the culture broth of a strain of Pseudomonas sp. These antibiotics were isolated as a complex by column chromatographies on Diaion HP-20 and silica gel, and then separated by HPLC. They are amphoteric in nature. The hydrochlorides are obtained as colorless powders, soluble in methanol and alkaline water. From their physico-chemical properties, these antibiotics are presumed to be acyloctapeptides containing a lactone linkage, and their differences occur in amino acid and fatty acid residues. The antibiotics are active against Gram-positive bacteria in vitro and in vivo.     

Isolation and characterization of katanosins A and B

Two peptide antibiotics katanosins A and B were isolated from the culture broth of a strain related to the genus Cytophaga. These antibiotics are basic peptides soluble in aqueous alcohols. The molecular formulae C57H95N15O17 for A and C58H97N15O17 for B were indicated. The constituent amino acids of katanosin A are suggested to be Thr (1), Ser (1), Val (1), Leu (3), Arg (1) and three unusual amino acids. In katanosin B, the Val residue is replaced by Ile. Katanosins A and B are active against Gram-positive bacteria in vitro and in vivo.