抗结核药物的作用机制及结核分枝杆菌的耐药机理

结核病是一个严重的全球性疾病,随着艾滋病病毒及耐药结核菌的出现及播散成为结核病控制的又一个威胁。虽然我们有结核疫苗及抗结核药物,但控制结核病仍是一件很棘手的事情。多重耐药结核菌的不断出现给结核病的治疗带来很大的困难。为有效控制耐药结核病,我们必须了解结核菌的耐药机理。本文讨论了抗结核药物的作用机制及结核菌的耐药机理。结核菌耐药机理的阐明对耐药菌的快速分子诊断及新药的开发有重要的意义。     

抗结核病药物的现状与研究进展

结核病是由结核分枝杆菌引起的一类严重的传染病,近年来结核分枝杆菌耐药株的传播导致治疗选择逐渐缩小,全球结核病防治形势依旧十分严峻。药物是目前治疗结核的主要手段,新型抗结核药物的研发旨在为临床提供克服耐药、疗程更短、患者依从性更好的治疗方案。近年来该领域取得了重要进展,包括首个新机制抗结核药物贝达喹啉获批上市,以及多种新机制、新结构的抗结核候选药进入临床试验阶段,这为耐药结核病治疗开拓了新的前景。本文将对现有抗结核病药物及新药研究进展进行综述。     

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。     

功能基因组学和组合化学在抗结核新药开发中的应用

结核病耐药性是导致结核病难以治愈的重要原因。为根除结核病，必须开发针对耐药菌和休眠菌的新型抗结核病药物，组合化学和功能基因组学的结合将有助于加快新药开发速度。本文综述了功能基因组学和组合化学在开发抗结核新药中的应用。     

抗结核病化疗药物研究的新进展

结核病是由结核分枝杆菌感染引起的,是全球重大人类传染病之一。现有用于抗结核病的化疗药物,品种少、选择余地小、治疗疗程长且不良反应严重。多药耐药和广药耐药结核分枝杆菌的出现使全球抗结核的形势日益严峻,开发疗效好、不良反应小且不易耐药的新型抗结核药物迫在眉睫。近10年来,抗结核化疗新药研发取得了较明显进展。作者对近年来抗结核病化疗药物的研究进展作一综述。     

抗结核药物的临床应用及不良反应

结核病是由结核分枝杆菌引起的慢性传染病,可侵及许多脏器、以肺部受累形成肺结核最为常见。目前在全球范围内由于耐药结核菌的产生与扩展,结核菌与人体免疫缺陷病毒(HRV)的双重感染以及许多国家结核病控制规则不完善,使全球结核病菌呈明显上升趋势。抗结核化学药物治疗对控制结核病起决定性作用,合理化疗可使病灶内细菌消灭最终达到痊愈。但抗结核药物存在许多不良反应,可造成严重后果.甚至危及生命,因此正确对待抗结核药物的作用及不良反应,有利于提高药物疗效的临床治愈率。     

抗结核病新药作用分子机制研究进展

结核菌耐药现象越来越严重,开发治疗结核病的新药非常紧迫。全球药物研发的一个明显趋势是整合分子生物学及功能基因组方法学,结核病治疗药物的研发也如此。本文综述结核病新药分子靶标的鉴定、分子作用机理与耐药机理以及几种前景较好抗结核新药的药物学特征,并重点概括其应用及研究的最新成果。这将有助于结核病新药研发。     

抗结核分枝杆菌持留菌的药物研究进展

持留态结核分枝杆菌具有对现有抗结核药物表型耐药的特征,是结核病病程迁延和复发的主要原因.因此,研发抗结核分枝杆菌持留菌的药物,对缩短抗结核治疗疗程,减少耐药性发生意义重大.本文就结核分枝杆菌持留菌的耐药机制、PA-824等新药的研究进展以及筛选评价模型进行简要综述,为抗结核分枝杆菌持留菌药物的研究提供参考.     

抗结核药物靶点研究最新进展

近年来结核病又卷土重来,发病率与死亡率明显回升,并且结核菌的耐药问题也日趋严重,成为结核病临床治疗的棘手问题,而在过去的30年里未开发出新型高效的抗结核药物.因此发现潜在的新抗结核药物靶点,研究开发新型抗结核药物,以实现对结核病的有效控制迫在眉睫.文中阐明了抗结核药物与胞壁合成相关的新靶点、与抗耐药有关的新靶点、与核酸稳定性相关的靶点、与电子传递及氧化还原相关的靶点,研究未知作用机制有效物质而发现的新靶点以及与重要代谢途径中关键代谢酶相关的靶点等6个方面研究的新进展,对抗结核新药的研究具有重要指导意义.     

氟喹诺酮类药物的抗结核作用

结核病化疗的出现使结核病治疗发生了划时代的改变。据估计［１］,目前全球约有２０亿人感染了结核分支杆菌,每年有８００万新患者出现,３００万人死于结核病,约５０００万人携带结核分支杆菌耐药菌株。结核菌耐药已成为当今结核病控制所面临的一大难题,迫切需要抗结核新药的出现。氟喹诺酮类药物抗结核分支杆菌的作用引入瞩目,成为新药开发研究中的一个主要方向,其中环丙沙星、氧氟沙星、左氧氟沙星、司帕沙星已用于临床结核治疗,现综述如下。ｌ　作用机制　　　　氟喹诺酮类药物主要作用于细菌的脱氧核糖核酸（ＤＮＡ）旋转酶（拓…     

Emerging therapeutic targets in tuberculosis: post-genomic era

Every minute, somewhere in the world four people die from tuberculosis (TB), yet it has been nearly 40 years since a novel drug was introduced to treat this disease. The ever increasing number of TB cases together with the advent of multi-drug resistant (MDR) TB, has stimulated the search for novel anti-TB agents. An array of novel drug targets is provided by the mycobacterial cell wall, whose integrity is essential for bacterial viability. Over the years researchers have identified potential drug targets that are associated with the synthesis of various cell wall constituents. This classic approach, together with the unravelling of the Mycobacterium tuberculosis genome sequence, has placed TB drug research in an unprecedented position. An entire new set of genetic and bioinformatic tools for probing potential drug targets is now available. As therapies using first-line drugs like isoniazid (INH) or rifampin in combination with second-line drugs, like ethambutol (EMB) still continues, a number of substituted fluoroquinolones are being considered as the new generation of anti-TB drugs for their favourable pharmacokinetic profile and excellent oral bioavailability. In this review, the future of anti-TB drugs is discussed with reflection on the structure and biosynthesis of cell wall constituents that are potential drug targets. The importance and relevance of the M. tuberculosis genome sequence for the development of novel anti-TB drugs, have also been underscored.     

New anti-tuberculosis therapies

Tuberculosis (TB) is one of the most important global health problems in today's world. Poverty, inadequate health services, drug resistance and HIV/AIDS epidemic has hampered TB control, mostly in the developing nations, despite the worldwide availability of rifampicin-containing regimens with high antimycobacterial efficacy. Pharmaceutical companies have neglected the development of new anti-TB drugs in the last decades due to a lack of market incentives, while the public sector held only a meagre interest on TB control. However, novel initiatives, especially those merging in the Global Alliance for TB Drug Development, a public–private non-profit organisation backed by the World Health Organization, and a renewed interest in the research on Mycobacterium tuberculosis, have changed the TB pipeline in the last few years. At present, an unexpected number of new compounds are being developed in order to launch shorter and more efficient anti-TB therapies. This is the most active pipeline for TB drug development in known history.     

Stereochemistry at the forefront in the design and discovery of novel anti-tuberculosis agents

Today, 75% of new drugs introduced to the market are single enantiomers and new techniques in asymmetric synthesis and chiral separation expedites chiral drug discovery and development worldwide. The enantiomers of a chiral drug present unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of chiral drugs determines their pharmacokinetic, pharmacodynamic, and toxicological actions. Thus, it is imperative that only the pure and therapeutically active isomer be prepared and marketed. Tuberculosis (TB), a highly contagious and airborne disease that is caused by infection with Mycobacterium tuberculosis (Mtb), currently represents one of the most threatening health problems globally. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), as well as HIV co-infection along with a lengthy treatment regimen, highlights an urgent need for the development of new anti-TB agents. Currently, new chiral anti-TB agents are being developed from some well-known anti-TB agents, high throughput screening (HTS) hits, and natural products. This review will focus on the reported chiral anti-TB agents together with the clinical importance of their chirality and stereochemistry.     

Newly developed drugs invented to treat tuberculosis in clinical trial

Tuberculosis (TB) is a leading cause of morbidity and mortality in more than one-third of the world population. Its impact on global health is a result of decades of neglect for such an important infectious disease, lack of resources for national TB control programs, poor case detection, and inadequate/inappropriate therapy in high-burden countries. The worldwide dissemination of multidrug (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis poses a serious threat to human health due to inadequacy of long and cumbersome tuberculosis (TB) therapy. Treatment regimens consist of at least four drugs with different mechanisms of action. Several new molecules in clinical development hasencouraged the scientific community to discover new drug targets and new drug candidates. Therefore, new drugs are urgently needed to shorten and improve the treatment course in drug resistant TB, and to minimize the occurrence of new infections and death. Nowadays, various new investigational drugs, such as bedaquine (TMC207), nitroimidazoles (PA-824, OPC-67683), diamines (SQ109), oxazolidinones (Linezolid, PNU-100480 (Sutezolid), ADZ5847), pyrroles (LL3858) and fluoroquinolones (moxifloxacin and gatifloxacin), have entered clinical trials and are in progress to be developed for the treatment of MDR-TB. In this perspectivearticle, an overview of the new anti-TB drugs with different structures that are either being clinically used or in advanced stages clinical stages as well as of preclinical development are presented. This review provides snapshots of the efforts that are being made in the development of new drugs as lead anti-TB agents. Finally, it is crucial to improve the connection between research and development institutes, industries, drug control authorities, and international policy-making bodies to deliver efficacious therapies for patients who are suffering from TB.     

Tuberculosis drug targets

Despite the availability of the BCG vaccine and chemotherapy, tuberculosis (TB) remains a leading infectious killer worldwide. The recent rise of TB and especially the alarming increase of drug-resistant TB call for urgent need to develop new anti-TB drugs. Lengthy chemotherapy and increasing emergence of drug-resistant strains pose a significant problem for effective control. The need for a lengthy TB therapy is a consequence of the presence of persistent Mycobacterium tuberculosis, not effectively killed by current anti-TB agents. A list of new drug candidates along with proposed targets for intervention is described. Recent advances in the knowledge of the biology of the organism and the availability of the genome sequence provide a wide range of novel targets for drug design. Gene products involved in controlling vital aspects of mycobacterial metabolism, persistence, virulence and cell wall synthesis would be attractive targets. It is expected that the application of functional genomics tools, such as microarray and proteomics, in combination with modern approaches, such as structure-based drug design and combinatorial chemistry to biology-based targets, will lead to the development of new drugs that are not only active against drug-resistant TB but also can shorten the course of TB therapy.     

The treatment of tuberculosis: current status and future prospects

Although a vaccine and effective chemotherapy against tuberculosis (TB) have been available for more than half a century, TB was declared a global emergency in 1993. Current chemotherapeutic regimens are being undermined by lack of resources for proper implementation and control, and the emergence of multi-drug resistant strains of Mycobacterium tuberculosis. Several new chemotherapeutic agents are under development, mainly derived from existing anti-TB drugs or broad-spectrum antibiotics. New experimental agents include immunomodulants and drugs directed against novel cellular targets.     

Opportunities for overcoming tuberculosis: Emerging targets and their inhibitors

Tuberculosis (TB), an airborne infectious disease mainly caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of human morbidity and mortality worldwide. Given the alarming rise of resistance to anti-TB drugs and latent TB infection (LTBI), new targets and novel bioactive compounds are urgently needed for the treatment of this disease. We provide an overview of the recent advances in anti-TB drug discovery, emphasizing several newly validated targets for which an inhibitor has been reported in the past five years. Our review presents several attractive directions that have potential for the development of next-generation therapies.     

Current status of some antituberculosis drugs and the development of new antituberculous agents with special reference to their in vitro and in vivo antimicrobial activities

Tuberculosis (TB) is a growing international health concern, since it is the leading infectious cause of death in the world today. In particular, the increasing prevalence of multidrug-resistant (MDR)-TB has greatly contributed to the increased difficulties in the control of TB. Because of the global health problems of TB, the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new anti-TB drugs without cross-resistance with known antimycobacterial agents is urgently needed. This article deals with the following areas. First, it briefly reviews some recent findings on the pharmacological status of fluoroquinolones and rifamycin derivatives. Second, it describes other types of new agents, such as oxazolidinones (linezolid, PNU-100480), nitroimidazoles (nitroimidazopyran PA-824, metronidazole), 2-pyridone, riminophenazines and diarylquinolines, which are being developed as anti-TB drugs. In addition, the future development of new antitubercular drugs is briefly discussed according to the potential pharmacological targets. New critical information on the whole genome of Mycobacterium tuberculosis (MTB) was recently elucidated and increasing knowledge on various mycobacterial virulence genes will promote the progression in the identification of genes that code for new drug targets. Using such findings on MTB genome, drug development using quantitative structure-activity relationship may be possible in the near future.     

Emerging drugs and alternative possibilities in the treatment of tuberculosis

Introduction: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB.

Areas covered: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB.

Expert opinion: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment.

The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation.

Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.