抗结核药物的研究进展（二）

结核病仍为最具破坏性的细菌性疾病之一，发病率和死亡率都很高。结核分枝杆菌能侵入宿主免疫系统，在肺肉芽肿中持留，致使目前的抗结核药物无法杀灭菌体。近年来药物耐受以及伴有HIV感染的结核病发病率急剧增加都给结核的控制带来了很大的困难，迫切需要深入了解目前抗结核药物的作用机制及耐药机制、病菌繁殖的分子机制，以指导开发对持留菌和耐药菌更加有效的新型药物。文中介绍了近年来从现有药物中发现的具有抗结核活性的化合物，以及一些有开发潜能的抗结核药物靶点。     

Progress in the research of antituberculous drugs(I)

结核病仍为最具破坏性的细菌性疾病之一，发病率和死亡率都很高。结核分枝杆菌能侵入宿主免疫系统，在肺肉芽肿中持留，致使目前的抗结核药物无法杀灭菌体。近年来药物耐受以及伴有HIV感染的结核病发病率急剧增加都给结核的控制带来了很大的困难，迫切需要深入了解目前抗结核药物的作用机制及耐药机制、病菌繁殖的分子机制，以指导开发对持留菌和耐药菌更加有效的新型药物。文中综述了近年来通过天然物筛选、新药设计合成以及对现有抗结核药物的再修饰等途径，发现的一些有抗结核活性的化合物，以及结核杆菌分子生物学和抗结核治疗靶点的研究进展。     

以异柠檬酸裂解酶为靶点筛选抗持留结核分枝杆菌药物

进入21世纪，结核病仍然是临床上发病率和死亡率最高的传染病之一。目前，结核分枝杆菌（Mycobacterium tuberculosis）的多重耐药，以及在抗结核药物作用过程中结核分枝杆菌的持留状态，已成为全世界结核病控制工作的主要障碍。异柠檬酸裂解酶（isocitrate lyase，ICL）是乙醛酸循环途径中的关键限速酶之一，决定了结核分枝杆菌的持留性。在文中我们将描述异柠檬酸裂解酶的基本性质及结构特征，希望能通过对ICL抑制剂作用区域的了解来推动抗持留结核分枝杆菌药物的研究。     

耐药肺结核患者结核分枝杆菌菌型分布及耐药研究

目的 研究肺结核耐药患者结核分枝杆菌菌型分布及耐药情况。方法 收集2011年4月至2012年7月肺结核患者痰液标本,分离培养后进行菌种鉴定和药敏试验。结果 人结核分枝杆菌约占83.91%,牛结核分枝杆菌约占15.70%;患者对一线抗结核药物耐药率显著高于对二线抗结核药物耐压率,差异有统计学意义(P<0.05);一类抗结核药物单一耐药率显著高于二类抗结核药物(χ²=4.281,P<0.05)。结论 肺结核耐药患者菌型以人结核分枝杆菌最多,对一线抗结核药物的耐药率显著高于对二线抗结核药物的耐药率。     

卷曲霉素作用机制和耐药机制的功能基因组学研究进展

随着一线抗结核药物的长期和广泛使用，结核病耐药性亦不断增加，其中耐多药结核分枝杆菌和持留菌感染已经成为结核病有效防治的关卡。寻找新型抗结核药物迫在眉睫。卷曲霉素被认为是较理想的二线结核病治疗药物，也是开发新的肽类结核病药物的模板。本文综述了从功能基因组学角度研究卷曲霉素的生物合成基因簇、转录组水平的作用机制和细菌耐药新机制，为合理使用卷曲霉素和开发新一代肽类抗生素提供借鉴。     

《国外医药抗生素分册》第28卷1-6期（2007年）目次检索

药研动态极端环境微生物源活性物质的研究进展(综述)28(1):1喹诺酮诱发关节病的致病机理(编译)28(1):6解脲脲原体耐药机制研究进展(综述)28(1):10铜绿假单胞菌对β-内酰胺类抗生素的耐药机制和检测方法(综述)28(1):14微生物来源的受体拮抗剂研究进展(综述)28(1):19Ser/Thr蛋白激酶信号转导系统——抗结核药物筛选的新靶(综述)28(2):50抗结核分枝杆菌持留菌的药物研究进展(综述)28(2):56结核分枝杆菌中的复苏促进因子(综述)28(2):61分枝杆菌的多相分类鉴定(综述)28(2):64治疗结核新药和药物作用靶位(编译)28(2):70结核病的现行疗法和新药开…     

结核分枝杆菌药敏试验结果分析

目的探讨结核分枝杆菌依赖抗结核药物的发生率及特点。方法采用绝对浓度间接法对1522株分枝杆菌（结核分枝杆菌1450株,非结核分枝竿菌72株）进行7种药物的敏感性试验,药物依赖判定：在含抗结核药物的L-J培养基上生长旺盛程度和菌量,高浓度药物培养基≥低浓度药物培养基≥对照培养基。结果1450株结核分枝杆菌和72株非结核分枝杆菌共检出依赖菌330株（21、6％）。其中依赖异烟肼110株（7、23％）,依赖利福平260株（17、8％）,依赖链霉素（7、10％）,同时倚赖2种药物者148株（9、72％）。结论药物依赖现象均发生自耐多药菌株,尚未发现非结核分枝杆菌及初始耐药菌药物依赖。     

97株肺结核分枝杆菌体外药敏试验结果分析

目的 探讨肺结核分枝杆菌对常用抗结核药物的体外耐药性和耐药特点,为临床治疗提供参考。方法 采用绝对浓度间接法对2002年-2004年97株结核分枝杆菌进行4种抗结核杆菌药物体外药敏试验,并进行统计分析。结果 分析杆菌对所测的4种抗结核药物.总耐药率为42．3％,初始耐药率为41、5％,复治耐药率为46．7％,对RFP耐药率最高（90．5％）,最低的为EMB（24．4％）,非结核分枝杆菌耐多药率为100％。结论 我们应加强分枝杆菌对药物耐药性的监测,并进行菌型鉴定,选用敏感药物进行有规则和全程化疗,努力降低结核病的耐药率。     

乙胺丁醇技术鉴定会在上海举行

乙胺丁醇的鉴定会于1976年6月18日在上海举行。乙胺丁醇是对多种结核分枝杆菌有制菌作用的药物,其对结核杆菌最低制菌浓度的变异较小,发生耐药性的速度亦远较其他抗结核药物为慢,在临床应用中以其结构特殊,与其他抗结核药物很少有交叉耐药现象,因而对其他抗结核药物已发生耐药性的结核菌株,对乙胺丁醇仍然敏感。     

251株耐多药结核分枝杆菌二线药耐药结果分析

目的了解耐多药结核分枝杆菌对二线抗结核药物的耐药情况。方法采用绝对浓度间接法检测251株耐多药结核分枝杆菌临床分离株对二线抗结核药物的耐药性,回顾性分析其耐药情况。结果 251例耐多药结核分枝杆菌分离株对二线抗结核药物耐药率从高到低为:左氧氟沙星>丙硫异烟胺>对氨基水杨酸>力克肺疾>丁胺卡那霉素>卷曲霉素,其中初治耐药率依次为:13.5%、7.2%、6.8%6、.4%、4.0%和2.4%;复治耐药率分别为42.2%、22.7%2、2.3%、21.9%1、5.5%和4.0%;以左氧氟沙星耐药率为最高。中、青年组耐药率共占74.5%。结论耐多药结核分枝杆菌对二线药物耐药情况严重,给耐多药结核病患者治愈带来严峻挑战。     

New drug candidates and therapeutic targets for tuberculosis therapy

Despite advances in chemotherapy and the BCG (Bacillus Calmette-Guérin) vaccine, tuberculosis remains a significant infectious disease. Although it can be cured, the therapy takes at least 6-9 months, and the laborious and lengthy treatment brings with it dangers of noncompliance, significant toxicity and drug resistance. The increasing emergence of drug resistance and the problem of mycobacterial persistence highlight the need to develop novel TB drugs that are active against drug resistant bacteria but, more importantly, kill persistent bacteria and shorten the length of treatment. Recent new and exciting developments in tuberculosis drug discovery show good promise of a possible revolution in the chemotherapy of tuberculosis.     

细菌药物主动外排系统在生物被膜耐药中的作用

摘要：细菌生物被膜的产生使传统抗菌药物难以对其进行有效的清除,进而导致严重感染的复发和持续性感染, 是人类目 前面临的又一新的挑战。生物被膜细菌中由于营养物质和代谢产物的积累,促使药物主动外排系统相关基因表达明显增加, 使 外排泵转运多种不同类型的化合物能力增强,从而产生多重耐药表型,是引起细菌耐药的主要机制之一;外排泵基因的表达对 生物被膜细菌的生长和耐药性增强方面有着重要作用。本文从生物被膜耐药的影响因素、药物主动外排系统参与生物被膜形成 及其影响、外排泵抑制剂对生物被膜耐药的影响几个方面对细菌药物主动外排系统在生物被膜耐药中的作用进行综述。     

Results of antimicrobial susceptibilities of strains clinically isolated at 8 institutions in Hiroshima City to major oral antimicrobial drugs, mainly new quinolone drugs. Hiroshima Levofloxacin Susceptibility Surveillance Group

To evaluate the resistance for major oral antimicrobial agents, mainly new quinolones, we carried out a drug susceptibility surveillance of 3,050 strains of 11 microbial species clinically isolated at 8 institutions such as general hospitals and examination centers in Hiroshima city. 10 antimicrobial agents were used: 3 new quinolone drugs, 5 beta-lactam drugs, minocycline and clarithromycin. Among Gram-positive bacteria, methicillin resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis showed low susceptibility to the new quinolone drugs, while methicillin susceptible Staphylococcus aureus (MSSA) and Streptococcus pneumoniae were highly sensitive to these drugs. Among Gram-negative bacteria, Pseudomonas aeruginosa showed high resistance for the new quinolone drugs, but enteric bacteria and Haemophilus influenzae did not show marked resistance, maintaining almost good sensitivity to these drugs. To reduce the appearance of resistant bacteria, appropriate antimicrobial agents should be selected. Drug susceptibility surveillance in the community will be also important in the future.     

Tuberculosis therapy for 2016 and beyond

Introduction: Tuberculosis has been and remains arguably the most important infectious disease of all time. However, when compared to other diseases of similar human impact, relatively little progress has been made. Although there are many new drugs being developed for the first time in decades, it is unclear what role each of these new drugs will play.

Areas covered: The history of current therapy is reviewed as are the challenges associated with medications currently in use. Drugs that have recently been added to the armamentarium of therapy are reviewed as well as new candidate drugs.

Expert opinion: Developing new drugs to treat tuberculosis is of critical importance but even more important is developing strategies that ensure that there is no further amplification of drug resistance around the world especially in high burden low resource settings. Directly observed therapy is the cornerstone of protecting existing and future regimens and new technologies will potentially extend the reach of monitored therapy. Challenges remain including maintaining an adequate drug supply but the greatest challenge may be the issue of persistent organisms that require prolonged therapy. By discovering the triggers of persistence and identifying new drug targets can it be possible to radically shorten therapy.     

三氧化二砷联合用药治疗乳腺癌的研究进展

乳腺癌是女性发病率最高的恶性肿瘤之一。药物治疗和放射疗法是乳腺癌临床治疗的主要手段,但仍存在副作用大,肿瘤易耐药等问题。三氧化二砷是治疗急性早幼粒细胞白血病的一线用药,其也可联合多种药物对乳腺癌等实体瘤产生良好疗效,并在一定程度上缓解临床治疗弊端。本文综述三氧化二砷联合化疗药、激素类药、营养补充剂类药、中药等多种药物或放射疗法对乳腺癌的研究进展,为乳腺癌联合用药研究提供新思路。     

Programs to facilitate tuberculosis drug discovery: the tuberculosis antimicrobial acquisition and coordinating facility

There is a real need to discover new drugs that are active on drug-resistant tuberculosis (TB), and for drugs that will shorten the time of therapy. Large pharmaceutical companies have traditionally led the quest for discovering and developing new antiinfective agents but this is not the case when it comes to diseases like tuberculosis that primarily occur in resource restricted countries. Throughout the world many research groups are actively engaged in the scientific discovery of new TB drugs. Unfortunately, most research laboratories do not have the necessary safety facilities or resources for all facets of TB drug discovery. The Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) was established in order to make comprehensive testing services available at no cost to research laboratories with an interest in discovering new TB drugs. The TAACF is a consortium of contracts managed and funded by the National Institute of Allergy and Infectious Diseases (National Institutes of Health, Bethesda, MD) as a resource to support preclinical drug discovery and development. The core of the TAACF is the Southern Research Institute, Birmingham, AL, which supports compound acquisition, storage, medicinal chemistry, and high throughput assays. Other collaborating groups provide biological data on antimycobacterial activity and cytotoxicity, preliminary in vivo toxicity, oral bioavailability and efficacy in animal models, specialty testing (such as activity against non-replicating persistent bacteria), and assistance in technology transfer for developing comprehensive promotional packages and facilitating partnerships with pharmaceutical companies for drug development. The TAACF program and recent progress that has been publicly disclosed by suppliers is reviewed. There are many aspects promising of the program that will not be discussed due to confidentially.     

The future challenges facing the development of new antimicrobial drugs

The emergence of resistance to antibacterial agents is a pressing concern for human health. New drugs to combat this problem are therefore in great demand, but as past experience indicates, the time for resistance to new drugs to develop is often short. Conventionally, antibacterial drugs have been developed on the basis of their ability to inhibit bacterial multiplication, and this remains at the core of most approaches to discover new antibacterial drugs. Here, we focus primarily on an alternative novel strategy for antibacterial drug development that could potentially alleviate the current situation of drug resistance--targeting non-multiplying latent bacteria, which prolong the duration of antimicrobial chemotherapy and so might increase the rate of development of resistance.     

抗革兰阳性细菌药物研究进展

近20多年来,革兰阳性菌的感染和耐药日益增加,正在成为威胁人类健康的重大临床难题,人们需要寻求更有效的抗菌药物。近年来新的抗革兰阳性菌感染药物取得了不少进展,如新的糖肽类、链阳霉素类、脂肽类、恶唑烷酮类、新一代氟喹诺酮类等药物不断问世,为人类与细菌的斗争提供了有力的武器。     

Leishmaniasis: efflux pumps and chemoresistance

Resistance of parasitic protozoa such as Leishmania to therapeutic drugs continues to escalate in developing countries. Treatment programs for human leishmaniasis are still based on pentavalent antimonials but resistance to these compounds has been a persistent problem. In many instances, resistance of the parasite is due to over-expressed ABC efflux pumps. In Leishmania different classes of ABC transporters extrude antimonials, azoles and folates resulting in drug-resistant phenotypes. Although some studies have focused on developing inhibitors against these resistant phenotypes, new efficient modulators that are able to inhibit drug efflux are needed.     

儿童呼吸道感染细菌的耐药性分析

目的 了解儿童呼吸道感染常见病原菌的分布及其耐药情况,以采取有效防控对策,为合理选用抗菌药物提供参考.方法 对本院2012年9月～2013年4月收治的320例儿科呼吸道感染患者的痰液及药敏试验结果进行统计分析.结果 320份标本共培养分离出细菌90株（占28.1％）,其中革兰阳性菌46株（占51.1％）,以肺炎链球菌和金黄色葡萄球菌为主;革兰阴性菌44株（占48.9％）,以肺炎克雷伯菌、大肠埃希菌为主.金黄色葡萄球菌对青霉素的耐药率高达100.0％,肺炎链球菌对头孢呋辛的耐药率高达97.0％;主要革兰阴性菌对妥布霉素、氨苄西林等抗生素高度耐药,对亚胺培南的耐药率为0.0％;铜绿假单胞菌对氨苄西林耐药率为100.0％.结论 儿童呼吸道感染患者有多重耐药菌感染的可能,临床医师应根据药敏试验结果合理选用抗菌药物,因此,减少新的耐药菌产生和合理使用抗生素是非常重要的.