新的抗MRSA β-内酰胺类抗生素

Ceftobiprole medocaril是目前研究进展最快的治疗耐甲氧西林金葡菌(MRSA)感染的β-内酰胺类抗生素,现已完成首次Ⅲ期临床试验,并证实其疗效与万古霉素相当.同样具有抗MRSA活性的一种广谱头孢菌素类抗生素前药PPl0903(注射用)和一种碳青霉烯类抗生素RO4908643也已开始进入Ⅱ临床试验.     

儿茶素类化合物增强β-内酰胺类抗生素抗MRSA的作用

目的确定儿茶素类化合物——儿茶素(C)、表儿茶素没食子酸酯(ECG)、表没食子酸儿茶素(EGC)联合增强β-内酰胺类抗生素对耐甲氧西林的金黄色葡萄球菌(MRSA)产生抗菌增敏作用的最佳配伍比并对其可能的抗菌增敏作用的机制进行初步探讨。方法以微量稀释法测定C、ECG、EGC和几种β-内酰胺类抗生素单独对MRSA WHO-2菌株的最小抑菌浓度(MIC),以棋盘法测定C、ECG和EGC联合β-内酰胺类抗生素后对MRSA WHO-2菌株和25株MRSA临床分离株的最小抑菌浓度(MIC);以荧光分光光度计法和激光共聚焦扫描显微镜法观察C、ECG、EGC单独、两两联合、三者联合后对柔红霉素在MRSA WHO-2菌株菌体聚集的影响。结果 C、ECG、EGC三者联用时可以增强苯唑西林抗MRSA WHO-2菌株的能力,其中C、ECG、EGC按照1:1:1的比例配伍后可以取得最佳的抗菌增敏效果,后续实验选用此药物配伍。药物总浓度为16μg/mL的C2E(C+ECG+EGC)与苯唑西林、头孢唑林、氨苄西林联合时对于MRSA WHO-2菌株可产生抗菌增敏作用,对应的FIC指数均为0.38,同样浓度的C2E联合苯唑西林、氨苄西林、头孢唑林、头孢吡肟、泰能后对25株MRSA临床分离株中可产生抗菌增敏作用的菌株数所占比例分别为80%、76%、88%、80%、92%,说明C2E在MRSA临床分离株中同样存在广泛的抗菌增敏作用。经过均为16μg/mL的C、ECG、EGC三者联合处理后,MRSA WHO-2菌株菌体内的柔红霉素在荧光分光光度计下测得的A值为9.26±0.16,大于单独或两两联合处理时的A值(P<0.05),提示三者联合处理后增强了柔红霉素在MRSA WHO-2菌体内的聚集;激光共聚焦扫描显微镜法也显示出相同的结果。结论 C、ECG、EGC三者联合后可显著增强β-内酰胺类抗生素抗MRSA的作用,其最佳配伍比为1:1:1。抗菌增敏作用机制可能与其增加药物在菌体内的聚集有关。     

β-内酰胺酶抑制剂研究进展

细菌耐药问题日益严峻,已经引起了公众的广泛关注。β-内酰胺类抗生素是应用最广的抗生素,但是细菌对此类药物的耐药严重降低了药物的治疗效果,而产生β-内酰胺酶是β-内酰胺类药物耐药的主要机制,研制β-内酰胺酶抑制剂,以此作为增效剂与β-内酰胺类抗生素联用,可有效恢复细菌对β-内酰胺类药物的敏感性。临床上广泛传播的β-内酰胺酶有丝氨酸β-内酰胺酶和金属β-内酰胺酶。目前,在增效剂的研究中,已经获得了多种有效的丝氨酸β-内酰胺酶抑制剂,许多金属β-内酰胺酶抑制剂仍处于研究阶段。此外,为了应对由多种β-内酰胺酶引起的多重感染,研发丝氨酸β-内酰胺酶/金属β-内酰胺酶双重抑制剂也是逆转β-内酰胺类抗生素耐药性的新思路。本文综述了β-内酰胺酶抑制剂的研究进展,为研制新型β-内酰胺酶抑制剂提供借鉴。     

β-内酰胺药物及β-内酰胺酶相关的研究进展

摘要：抗生素的发明和使用给人类战胜病原菌感染提供了有力武器,然而因为抗生素的滥用,以细菌为代表的病原体通过进化产生抗性从而抵抗抗生素的杀伤作用。作为最早出现的一类抗生素,β-内酰胺类抗生素具有杀菌活性强、毒性低、适应症广及临床疗效好的特点,得到了广泛使用。细菌可以通过表达β-内酰胺酶来抵抗β-内酰胺药物的杀伤作用。随着微生物学、化学、药学等学科交叉发展,对β-内酰胺酶进行研究,开展对其检测分型并有针对性地开发其抑制剂对于克服细菌耐药,挽救患者生命有重要意义。     

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     

β-内酰胺类抗生素的作用机制

β-内酰胺类抗生素是迄今为止最有效而低毒的一类抗生素.关于这类抗生素和活细菌细胞的相互关系,人们提出了许多饶有兴趣的问题.诸如:β-内酰胺类具有什么样的结构特征才能引起选择性地抑制粘肽代谢?这类药物怎样通过细菌的外膜进入他们的生化靶部位?青霉素结合蛋白的功能是什么?粘肽代谢中对青霉素敏感酶有哪一些?青霉素分子如何抑制这些酶?这种抑制作用的细胞代谢和生理学结果又是什么?而最重     

β-内酰胺类抗生素药动学参数介绍

1985年6月23～28日,在日本京都召开了第14届国际化疗会议,从会议内容看,β-内酰胺类抗生素是目前最引人注意的研究课题,新品种不断出现。头孢菌素类除原有的抗菌谱广,抗菌活性强,对β-内酰胺酶稳定的特点外,更有长效及口第服三代新品     

β-内酰胺类抗生素的体外抗菌作用

本文报道17种β-内酰胺类抗生素对临床分离的424株革蓝氏阳性和阴性菌的体外抗菌作用.第一代头孢菌素和亚氨甲基thienamycin对多数革蓝氏阳性菌有强大抗菌作用,但对肺炎链球菌、化脓性链球菌和草绿色链球菌的活性并不优于青霉素类抗生素.肠球菌对头孢菌素类抗生素皆耐药,对亚氨甲基thienamycin比较敏感,半数菌株对脲基青霉素敏感.第三代头孢菌素和3种非典型β-内酰胺类抗生素对肠杆菌科细菌有极强抗菌活性,明显优于5种青霉素类抗生素和庆大霉素.流感杆菌对本实验采用的所有抗生素均敏感.硝酸盐阴性杆菌比较耐药,仅亚氨甲基thienamycin、Ceftazidime、头孢噻肟、头孢三嗪和哌拉西林对某些菌株有抗菌作用.多形模仿菌对5种青霉素类抗生素、第二代、第三代头孢菌素类抗生素(除头孢哌酮外)和亚氨甲基thienamycin敏感者约占半数.Ceftazidime对绿脓杆菌的作用最强,次为头孢哌酮和哌拉西林,再次为味苄青霉素、阿洛西林、Aztreonam、亚氨甲基thienamycin和头孢三嗪.除头孢哌酮外,第三代头孢菌素类抗生素和亚氨甲基thienamycin对产碱杆菌有较强活性.     

新型β-内酰胺酶抑制剂的合成及其活性研究

摘要：阿维巴坦是一种β-内酰胺酶抑制剂,最近与β-内酰胺酶抗生素头孢他啶联用被批准用于治疗复杂性腹腔感染和复杂 性尿路感染。它的成功案例鼓励了许多同系物的发展,其基础是其特殊的二氮杂环辛烷骨架。本文设计合成一系列新型具有二 氮杂环辛烷骨架的β-内酰胺酶抑制剂1~6,对β-内酰胺酶抑制剂1~6与头孢他啶抗生素联合使用时产生的抑菌活性进行了研究。 研究结果表明,与头孢他啶抗生素联用时对产生TEM-1、AmpC和KPC-2 3种β-内酰胺酶耐药菌表现出抑菌活性,使头孢他啶的 抑菌活性增强了2~4倍。     

β-内酰胺酶抑制剂复方制剂非临床研究技术指南

β-内酰胺酶抑制剂复方制剂在临床上被广泛应用于治疗耐药菌所致感染,由于早期β-内酰胺酶抑制剂的抑酶谱较 窄,抑酶谱更广泛的酶抑制剂在不断研发之中。与一般抗菌药物临床前研究不同,β-内酰胺酶抑制剂复方制剂的临床前研究需 明确β-内酰胺类药物或酶抑制剂本身的抗菌谱与抗菌活性,尤其是明确酶抑制剂是否具有抗菌活性。需要确定合适的β-内酰胺 类药物与酶抑制剂复方制剂,以及适用的不同酶型的目标病原菌。本文主要介绍新型β-内酰胺酶抑制剂复方制剂临床前研究方 法。临床前研究阶段的β-内酰胺酶抑制剂复方制剂研究包括体外研究和体内研究两部分,前者主要为体外药效学研究和体外药 动学/药效学(pharmacokinetic/pharmacodynamic, PK/PD)研究,常用研究方法包括β-内酰胺类药物和β-内酰胺酶抑制剂复方制剂最 低抑菌浓度测定、最低杀菌浓度测定、抗生素后效应测定及时间杀菌曲线。后者主要为动物药动学研究、感染动物药效学研究 和感染动物药动学/药效学研究。在动物药动学/药效学研究中,需考虑β-内酰胺类药物与酶抑制剂的相互影响。这些研究方法的 应用旨在阐明β-内酰胺酶抑制剂复方制剂两组分药效学特点、药动学相似与否、PK/PD指数及其临床前PK/PD靶值,为进入临 床试验阶段目标适应症及剂量选择提供依据。     

合成β-内酰胺酶抑制剂阿维巴坦的关键中间体的研究进展

β-内酰胺类抗生素耐药性是对目前全球卫生、食品安全和发展的重大威胁之一。由于新型抗生素开发难度不断增加,采用复方型抗生素就成为解决这一难题的重要手段。阿维巴坦是一类β-内酰胺酶抑制剂,其抑酶谱广,与其他β-内酰胺类抗生素联用可有效恢复或增强其活性,极大地缓解了针对耐药菌无药可用的局面。在几乎所有的合成路线中,都经历了一个重要的中间体：顺式-5-羟基哌啶-2-甲酸,然后由其再进一步衍生化后获得目标化合物。本文对顺式-5-羟基哌啶-2-甲酸的化学合成和酶促合成两种方式的研究现状和发展前景进行概述和总结,从而对其在医药合成领域中的应用提供参考。     

Neuroprotective effect of fucoxanthin on β-amyloid-induced cell death

Alzheimer’s disease (AD) is one of the most common cognitive disorders of the elderly. Fucoxanthin is a carotenoid that is found in common edible seaweed, and it is considered as a major active compound of marine algae with cancer-preventing,antioxidant and anti-inflammatory properties. In this study, we investigated the ability of fucoxanthin to protect against theβ-amyloid protein (Aβ)-induced neurotoxicity in primary cortical cultured neurons and PC12 cells. Neuroprotective effects of fucoxanthin were determined by measuring cell viability and nuclei double-staining with Hoechst 33342 and propidium iodide following Aβ treatment with or without fucoxanthin. Moreover, we also evaluated its potential mechanism on antioxidation by detecting the total antioxidant capacity (T-AOC), level of lipid peroxidation malondialdehyde (MDA) and activity of superoxide dismutase (SOD). We found that exposure of cortical cultured neurons or PC12 cells to Aβ resulted in neuronal cell death, whereas pre-treatment with fucoxanthin reduced Aβ-induced cell death. The data on the T-AOC, MDA level and SOD activity showed that Aβ treatment resulted in decreases in T-AOC and SOD activity and an increase in MDA level. After fucoxanthin administration, the results of T-AOC, MDA level and SOD activity showed an opposite trend, indicating that T-AOC was increased and MDA level was reduced. These results suggested that fucoxanthin prevented Aβ-induced neurotoxicity through attenuating oxidative stress induced by Aβ. Therefore, fucoxanthin might be useful as a potential preventive or therapeutic agent for AD.     

Clinical role of beta-lactam/beta-lactamase inhibitor combinations

The use of beta-lactamase inhibitors in combination with beta-lactam antibiotics is currently the most successful strategy to combat a specific resistance mechanism. Their broad spectrum of activity originates from the ability of respective inhibitors to inactivate a wide range of beta-lactamases produced by Gram-positive, Gram-negative, anaerobic and even acid-fast pathogens. Clinical experience confirms their effectiveness in the empirical treatment of respiratory, intra-abdominal, and skin and soft tissue infections. There is evidence to suggest that they are efficacious in treating patients with neutropenic fever and nosocomial infections, especially in combination with other agents. beta-Lactam/beta-lactamase inhibitor combinations are particularly useful against mixed infections. Their role in treating various multi-resistant pathogens such as Acinetobacter species and Stenotrophomonas maltophilia are gaining importance. Although, generally, they do not constitute reliable therapy against extended-spectrum beta-lactamase producers, their substitution in place of cephalosporins appears to reduce emergence of the latter pathogens. Similarly, their use may also curtail the emergence of other resistant pathogens such as Clostridium difficile and vancomycin-resistant enterococci. beta-Lactam/beta-lactamase inhibitor combinations are generally well tolerated and their oral forms provide effective outpatient therapy against many commonly encountered infections. In certain scenarios, they could even be more cost-effective than conventional combination therapies. With the accumulation of so much clinical experience, their role in the management of infections is now becoming more clearly defined.     

Understanding the longevity of the beta-lactam antibiotics and of antibiotic/beta-lactamase inhibitor combinations

Microbial resistance necessitates the search for new targets and new antibiotics. However, it is likely that resistance problems will eventually threaten these new products and it may, therefore, be instructive to review the successful employment of beta-lactam antibiotic/beta-lactamase inhibitor combinations to combat penicillin resistance. These combination drugs have proven successful for more than two decades, with inhibitor resistance still being relatively rare. The beta-lactamase inhibitors are mechanism-based irreversible inactivators. The ability of the inhibitors to avoid resistance may be due to the structural similarities between the substrate and inhibitor.     

Immobilization of β-glucuronidase: biocatalysis of glycyrrhizin to 18β-glycyrrhetinic acid and in-silico lead finding

The non-covalent immobilization of β-glucuronidase enzyme obtained from Rhizopus oryzae was carried outby entrapment in natural fiber (papaya and coconut).The bioconversion capability of immobilized enzyme was analyzed based on conversion ofglycyrrhizin to 18β-glycyrrhetinic acid under different conditions. The hydrolytic activity of the β-glucuronidase enzyme was highly depended on the microbial source and matrix, in which enzyme was immobilized. R. oryzae β-glucuronidase immobilized in papaya fibers produced the highest GA content (13.170 µg/mL) at 10 h of reaction. However R. oryzae β-glucuronidase immobilized in coconut fibers produced the highest GA content (21.425 µg/mL) at 15 h of reaction. Online Molinspiration software was used to predict drug like molecular properties of the 18β-glycyrrhetinic acid, and software suggested that the compounds had potential of becoming the orally active molecules. Therefore, in silico studies were conducted on proposed 18β-glycyrrhetinic acid to select the best possible drug candidates based on drug properties and bioactivity score of the compounds.     

抗MRSA感染新药的应用与研究进展

抗耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus,MRSA)感染和对多重耐药金黄色葡萄球菌的治疗一直是临床的严峻挑战.头孢洛林、达巴万星、特地唑胺和奥利万星是美国FDA最新批准的用于抗MRSA感染的药物,本文将对它们的结构特点与作用机制、体内外抗菌活性、不良反应以及临床应用与未来发展进行综述,并着重分析其特性和优劣势.