氨基糖苷类钝化酶耐药机制的研究进展

氨基糖苷类抗生素的耐药机制相当复杂，其中以产生钝化酶为主，近来对其研究较多，尤其是分子水平的研究取得了一些进展。本文对三种主要钝化酶即氨基糖苷磷酸转移酶、氨基糖苷乙酰转移酶、氨基糖苷类核苷转移酶的作用底物、作用位点、常见耐药细菌、编码基因等进行综述。     

卡那霉素B的酶—化学修饰

用酶—化学修饰的方法,对卡那霉素B的C_3~′位进行化学结构改造。利用耐药菌E.coliK.12 ML1629产生的钝化酶选择性地使卡那霉素B的C_3~′位羟基磷酸化,再用化学方法,将卡那霉素B-3~′—磷酸酯转化为3′—氯代—3′—去氧卡那霉素B,进而合成3′去氧卡那霉素B,即妥布拉霉素。     

核糖霉素的选择性环氨基甲酸酯保护

目的发展一种新的选择性环氨基甲酸酯保护策略，用以合成具有环氨基甲酸酯结构的新型核糖霉素衍生物。方法全苄氨羰基保护的核糖霉素在氢化钠作用下环合，通过控制反应条件选择性在不同位点引入环状氨基甲酸酯保护基。将苄氧羰基催化氢化脱除可得含有环氨基甲酸酯结构的核糖霉素衍生物。结果通过反应条件的控制成功地实现了核糖霉素的选择性环氨基甲酸酯保护。脱保护得到了的核糖霉素衍生物，但并没有预期的抗菌活性。结论含有环氨基甲酸酯的核糖霉素衍生物的合成表明选择性环氨基甲酸酯保护策略是方便可行的。具有环氨基甲酸酯结构的核糖霉素衍生物可能并不具有抗菌活性。     

氨基糖苷类抗生素衍生物的研究与进展

寻找耐酶,抗耐药菌,耳肾毒性低的衍生物已成为氨基糖苷类抗生素研究开发的重点,本文对氨基糖苷类抗生素的化学改造,生物合成和钝化酶抑制剂等方面的研究进展作了综合性介绍。     

氨基糖苷类抗生素的耐药机制及控制耐药性的策略

氨基糖苷类抗生素是高效，广谱抗生素，随着临床的广泛应用，细菌的氨基糖苷耐药性日趋严重，这在很大程度上降低了其临床应用的潜力，导致细菌氨基糖苷耐药性的因素包括；核糖体结合位点的变化；细菌对药物摄入及积累的降低，细菌产生使抗生素失活的钝化酶等，尤其对导致耐药性的最主要因素-氨基糖苷类抗生素钝化酶进行了较详细的论述，并根据耐药机制，从氨基糖苷类抗生素的结构改造，印化酶抑制剂及合理的临床用药等方面讨论了控制耐药性的策略。     

肠球菌对氨基糖苷类高水平耐药机制的临床研究进展

耐氨基糖苷类高水平肠球菌（HLAR）是医院感染的重要病原菌,氨基糖苷类修饰酶（AME）是肠球菌对氨基糖苷类高水平耐药的主要机制,其中N－乙酰转移酶（AAC）、O-核苷转移酶（ANT）和O-磷酶转移酶（APH）是参与耐药基因表达的主要氨基糖苷类修饰酶类。现就氨基糖苷类修饰酶的耐药基因及其耐药基因的传播进行临床研究,从而为减少医院HLAR感染的发生提供分子生物学依据。     

氨基糖苷类抗生素的耐药机制研究进展

氨基糖苷类抗生素(AG)是高效的广谱抗生素，用于治疗许多革兰阴性菌和一些革兰阳性菌感染，随着临床的广泛应用，细菌的耐药性日趋严重。本文主要从核糖体修饰作用、氨基糖苷类抗生素的修饰酶的作用、药物的外排泵系统等方面对 AGs的耐药机制进行阐述，为能合理使用AGs、控制细菌耐药性蔓延以及新型AG药物的开发提供参考。     

多重耐药大肠埃希菌氨基糖苷类修饰酶与Ⅰ类整合酶基因的研究

目的 探讨本地区临床分离多重耐药大肠埃希菌(Escherichia coli,E.coli)的氨基糖苷类修饰酶和Ⅰ类整合子基因存在情况.方法 纸片扩散法(K-B法)测定71株大肠埃希菌对常用抗菌药物的耐药性,应用PCR技术对E.coli进行氨基糖苷类修饰酶和Ⅰ类整合酶基因的检测.结果 71株大肠埃希菌对庆大霉素、左氧氟沙星、头孢噻肟、头孢他啶的耐药率分别分为66.20％、63.38％、59.15％、18.31％,其中23株为多重耐药株(32.39％).氨基糖苷类修饰酶基因aac(3)-Ⅱ阳性40株(56.34％),aac(6′)-Ⅰ阳性22株(30.99％),ant(3″)-Ⅰ阳性14株(19.72％),未检出aac(6′)-Ⅱ阳性株,氨基糖苷类修饰酶基因总检出率为74.65％;Ⅰ类整合酶基因(intI1)阳性53株(74.65％).多重耐药与非多重耐药大肠埃希菌中aac(3)-Ⅱ、aac(6')-Ⅰ、总氨基糖苷类修饰酶基因、intI1的阳性率有统计学差异(P＜0.05).结论 本地区多重耐药E.coli的氨基糖苷类修饰酶基因、Ⅰ类整合酶基因携带率高.     

应对氨基糖苷类抗生素耐药的策略

氨基糖苷类抗生素在治疗感染性疾病中起着重要作用,尤其是革兰阴性菌引起的严重感染,但是随着临床上耐药菌株的出现较大地限制了此类抗生素的应用,因此,在对细菌耐药机制研究的基础上如何控制细菌的耐药性成为一项迫切需要解决的任务。针对细菌对氨基糖苷类抗生素产生抗性的机制不同,目前采用的措施主要有3种：1）对原有氨基糖苷类抗生素进行改造;2）开发氨基糖苷类抗生素修饰酶抑制剂;3）设计双功能氨基糖苷类抗生素。     

环孢菌素A的酶促合成

环孢菌素A是一种具有抗炎、免疫抑制、抗真菌和抗寄生虫等各种生物活性的环状十一肽。由于环孢菌素A特殊的免疫抑制活性,可用于移植外科与自身免疫病的治疗,且在作为研究免疫系统机制的工具方面有重要意义。附图系环孢菌素A及其一些在2或8位上具有不同氨基酸的同系环孢菌素的结构。     

从发酵液中分离提取卡那霉素的新工艺研究

以卡那霉素发酵液为原料 ,通过比较不同类型阳离子交换树脂的吸附特性 ,筛选出卡那霉素B的吸附率高、杂质吸附量较低和卡那霉素吸附总量较高的D4阳离子交换树脂。确定了较佳的吸附富集条件为 :上柱发酵液的pH7.0 ,吸附流速 1.5v/(v·h) ;进一步确定较佳的除杂洗脱条件为 :硫酸铵溶液浓度 1.0 %(v/v) ,pH7.5 ,流速 1.2 5v/(v·h)除杂质。最后用 4%(v/v)氨水洗脱。经过在阳离子交换树脂上的吸附富集和除杂质后 ,可以将发酵液卡那霉素中约含 2 .5 %的卡那霉素B组分提高到 6%以上。通过采用多柱串联工艺流程 ,达到分离富集卡那霉素B组分 ,提高卡那霉素碱成品 (卡那霉素A碱 )纯度的目的     

丹参素结构中醇羟基的修饰与初步活性评价

目的设计合成系列在丹参素醇羟基部位修饰的新衍生物,初步探索醇羟基在丹参素生物活性中的作用。方法丹参素的酚羟基以及羧基经苄基保护后,其醇羟基与相应的基团在不同的催化剂下缩合生成醚键以及酯键化合物,然后脱除保护基得到醇羟基修饰的衍生物。通过体外的心肌细胞氧化损伤模型初步评价新衍生物的生物活性,分析其构效关系。结果合成了11个丹参素新衍生物,并进行了结构确证;活性实验显示,醇羟基上醚键与酯键修饰的衍生物活性均没有明显高于母药丹参素。结论裸露的醇羟基可能是丹参素发挥作用的必需基团。     

抗病毒药替比夫定衍生物的合成

目的 设计合成抗病毒药替比夫定的衍生物。方法 替比夫定与丁二酸酐反应,分别得到5′-羟基单酯化中间体和3′-羟基、5′-羟基双酯化中间体,两个中间体再分别与卤代烃反应生成两个系列的替比夫定衍生物。结果与结论 合成了两个系列共12个未见文献报道的新化合物,目标化合物的结构均经¹H-NMR、IR、MS谱确证。     

Synthesis of piscidinol A derivatives and their ability to inhibit HIV-1 protease

Four types of piscidinol A derivatives were synthesized and evaluated their ability to inhibit HIV-1 protease to understand their structure-activity relationships. Of these tirucallane-type triterpene derivatives, an A-seco derivative (1b) moderately inhibited human immunodeficiency virus (HIV) protease (IC₅₀ 38.2 μM). The 2,2-dimethyl succinic acid (DMS) acylated tirucallane derivatives (4b, 6a, and 7b, 50 < IC₅₀ < 100 μM) were more inhibitory against HIV-1 PR than the others (PA, 2a, 4a, 4c–4d, 5a, 6b–6d, and 7a, IC₅₀ > 100 μM). These findings indicated that the 2,3-seco-2,3-dioic acid (1b) and DMS-acylated tirucallane-type derivatives preferably inhibited HIV viral protease.     

Synthesis and biological activity of amide derivatives of ginkgolide A

Amide derivatives of ginkgolide A were prepared and evaluated for their in vitro ability to inhibit the PAF-induced aggregation of rabbit platelets. They showed less activities than their parent compound ginkgolide A.     

Synthesis and antitumor activity evaluation of lamiridosin A derivatives

A series of lamiridosin A derivatives were synthesized through simple procedures. Their antitumor activities were evaluated against EC9706, MGC803, and B16 cell lines in vitro. Several compounds showed potent antitumor activity, especially compound 10, with IC₅₀ value of 2.36 μmol/L against MGC803 cell lines, is more potent than marketed positive drug 5-fluorouridine (5-FU).     

紫杉烷类多药耐药逆转剂的合成及其逆转耐药活性紫杉烷类多药耐药逆转剂的合成及其逆转耐药活性

目的设计合成一系列新型紫杉烷类化合物并进行逆转多药耐药肿瘤细胞耐药活性的筛选。方法以本所生物合成的紫杉烷，Sinenxan A为原料，合成了10个(I_1～7, II_1,2, III)新的紫杉烷类化合物，其结构经FABMS，2DNMR确证，并对多药耐药癌细胞进行了逆转耐药性的试验。结果9个(I_2～7,II_1,2,III)化合物对多药耐药的人口腔上皮癌细胞KB/V200，能够显著逆转其耐药性，增强抗癌药的活性，其中化合物I₂, I₃, I₄逆转活性明显好于已知对照药Verapamil。结论紫杉烷类化合物作为多药耐药逆转剂有较好的逆转耐药活性，值得进一步研究。     

Induction of drug metabolizing enzymes by sulfinpyrazone

Summary A previous interaction study of sulfinpyrazone (Anturano®) suggested that it induced microsomal drug metabolizing enzymes in the liver. To verify this finding the effect of sulfinpyrazone 800 mg per day for four weeks was investigated in ten healthy volunteers. Both the therapeutic actions of sulfinpyrazone, the uricosuric and the antiaggregating effects, were demonstrated (p<0.05). The influence on the microsomal drug metabolizing system in the liver was demonstrated by an increase in serum--glutamyl transpeptidase from 15.1 to 23.3 U/l (p>0.05), a significant increase in the urinary excretion of d-glucaric acid (29.6 to 77.9 µMol/24 h,p<0.05) and an increase in antipyrine clearance from 50.3 ml/min to 83.9 ml/min (p<0.05). The possibility of enhancement of drug metabolism during treatment with sulfinpyrazone in combination with other drugs should be kept in mind.     

Synthesis of novel tetrandrine derivatives and their inhibition against NSCLC A549 cells

Abstract

A series of novel tetrandrine (Tet) derivatives were synthesized through Suzuki -Miyaura reaction and evaluated for their cytotoxicity against human non-small cell lung carcinoma (NSCLC) A549 cells. Interestingly, most of derivatives showed similar cytotoxicity to Tet against NSCLC A549 cells, and particularly, compounds Y5, Y6, Y9 and Y11 showed the most significant cytotoxic effects with IC₅₀ values ranging from 3.87 to 4.66 mM. The present study is expected to contribute to the future design of more effective anticancer agents in lung cancer chemotherapy.     

Inhibition of cyclosporin A/FK 506 resistant,lymphokine-induced T-cell activation by phenothiazine derivatives

Earlier studies from our laboratory have demonstrated that phenothiazine derivatives are capable of inhibiting mitogen-induced activation of human T-cells and thymocytes. Similar to cyclosporin A, phenothiazine derivatives exert these inhibitory effects by decreasing the accumulation of lymphokine-specific mRNA. However, proliferation of T-cell blasts and of unfractionated human thymocytes can also be induced by interleukin 2. Since activation of T-cells via the interleukin 2 receptor seems to be resistant to the action of cyclosporin A, the present study was designed to investigate whether lymphokine-induced activation could be inhibited by phenothiazine derivatives. The effects of the phenothiazine derivatives chlorpromazine and/or fluphenazine have been studied and compared to the action of cyclosporin A and in human thymocytes, human T-cell blasts and in the human T-cell line H 33-HJ JA 1, which is an interleukin 2 producing cell line derived from Jurkat cells. As evidenced by the incorporation of [³H]-thymidine, cyclosporin A (1 g/ml) and FK506 (100 ng/ml) have no or only marginal inhibitory capacity on interleukin 2-induced proliferation in all T-cell systems tested. By contrast, phenothiazine derivatives (fluphenazine > chlorpromazine) exert a dose-dependent inhibition of the activation of these cells in pharmacologically relevant micromolar concentrations. Similar results were obtained by measuring the production of interferon- in the supernatants of interleukin 2-induced human thymocytes. Our results suggest that the use of phenothiazines might be helpful in immunosuppressive regimens. Correspondence to: M. Schleuning at the above address