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。     

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。     

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。     

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。     

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。     

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.     

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。     

某院2013年抗结核药物的使用情况分析

<正>结核病是由结核分枝杆菌引起的慢性传染病,可侵及全身多个脏器,以肺部受累多见。结核病合理的化学药物治疗是控制疾病发展、复发及抑制结核杆菌耐药产生的关键[1]。目前用于临床的抗结核药种类很多,但由于不合理使用,近年来结核分枝杆菌的耐药率逐渐增加,且有些为耐多药菌株,因此抗结核药物的合理使用非常重要。我院为专门收治结核患者的医院,现对2013年我院抗结核药物的使用情况进行分析,以期为临床用药提供参考。     

抗结核药物的研究进展

目的介绍抗结核药物的最新研究进展,对一线抗结核药物、二线抗结核药物和新型抗结核药物进行总结。方法参考近年来国内外文献48篇对抗结核药物进行了综述。结果一线抗结核药物和二线抗结核药物在临床上广泛使用,但由于耐多药结核杆菌的出现,使其不能达到有效控制结核病的目的,新型抗结核药物在未来几年有可能弥补现有抗结核药物的不足而广泛应用于临床。结论现有的抗结核药物还不能满足患者的需要,仍需开发更为有效的新型抗结核药物。     

New anti-Mycobacterium agents: recent advances in patent literature

Mycobacterium tuberculosis is the greatest single infectious cause of mortality worldwide. In addition, disseminated infection with Mycobacterium avium complex (dMAC) is an increasingly frequent complication in advanced HIV infection. Among the different classes of anti-Mycobacterium compounds studied in the recent years, those of oxazolidinones and imidazole derivatives seem the most likely to provide new useful drugs for the clinical treatment of Mycobacterium infections in the future. Although the most important improvement in the therapy of tuberculosis infections will be obtained using antisense oligonucleotides and vaccines, the research of new ‘conventional’ antituberculous drugs will also remain an important challenge.     

Intensified antibiotic treatment of tuberculosis meningitis

Introduction: Meningitis is the most severe manifestation of tuberculosis, resulting in death or disability in over 50% of those affected, with even higher morbidity and mortality among patients with HIV or drug resistance. Antimicrobial treatment of Tuberculous meningitis (TBM) is similar to treatment of pulmonary tuberculosis, although some drugs show poor central nervous system penetration. Therefore, intensification of antibiotic treatment may improve TBM treatment outcomes.

Areas covered: In this review, we address three main areas: available data for old and new anti-tuberculous agents; intensified treatment in specific patient groups like HIV co-infection, drug-resistance, and children; and optimal research strategies.

Expert commentary: There is good evidence from preclinical, clinical, and modeling studies to support the use of high-dose rifampicin in TBM, likely to be at least 30 mg/kg. Higher dose isoniazid could be beneficial, especially in rapid acetylators. The role of other first and second line drugs is unclear, but observational data suggest that linezolid, which has good brain penetration, may be beneficial. We advocate the use of molecular pharmacological approaches, physiologically based pharmacokinetic modeling and pharmacokinetic-pharmacodynamic studies to define optimal regimens to be tested in clinical trials. Exciting data from recent studies hold promise for improved regimens and better clinical outcomes in future.     

Advances in molecular targets and chemotherapy of tuberculosis

The need for newer, effective drugs with different modes of action against tuberculosis is great, despite the numerous drugs in clinical use and the development of Bacilli Calmette-Guerin (BCG) vaccine. Three major goals should be considered in the development of new antituberculosis drugs: 1) they should be fast acting to reduce the long duration of treatment, thereby avoiding drug toxicity; 2) they should be active against both sensitive and resistant strains of tubercle bacilli; and 3) they should possess significant activity against dormant bacilli, which represent the stage affecting one-third of the world's tuberculosis patients. This review provides an overview of important current drugs, novel targets for the development of antituberculosis agents and future drug candidates.     

Mycobacterial shikimate pathway enzymes as targets for drug design

The aetiological agent of tuberculosis (TB), Mycobacterium tuberculosis, is responsible for millions of deaths annually. The increasing prevalence of the disease, the emergence of multidrug-resistant strains, and the devastating effect of human immunodeficiency virus co-infection have led to an urgent need for the development of new and more efficient antimycobacterial drugs. Since the shikimate pathway is present and essential in algae, higher plants, bacteria, and fungi, but absent from mammals, the gene products of the common pathway might represent attractive targets for the development of new antimycobacterial agents. In this review we describe studies on shikimate pathway enzymes, including enzyme kinetics and structural data. We have focused on mycobacterial shikimate pathway enzymes as potential targets for the development of new anti-TB agents.     

抗结核药物最新进展

结核病是病死率仅次于艾滋病的全球第二大感染性疾病。当前结核病的控制面临一系列挑战。世界卫生组织推荐的结核治疗方案疗程长,对敏感菌和耐药菌感染分别需6个月、20个月的持续治疗。现有抗结核一线化疗药仍为四十多年前所开发,品种有限,选择余地小。此外,多耐药结核病(MDR-TB)及广泛耐药结核病(XDR-TB)的流行,严重阻碍了结核病控制的进展。严峻的结核病防治形势急需抗结核新药的出现。近十年来,抗结核化疗新药研发在沉寂多年后取得了较明显进展。本文介绍了近年上市与处于临床及临床前研究阶段的抗结核新药。     

Recent developments in the treatment of tuberculosis

The history of chemotherapy of tuberculosis commenced in 1944 with the discovery of streptomycin. Currently, short-course chemotherapy comprising rifampicin, isoniazid, pyrazinamide and ethambutol/streptomycin administered under directly observed settings for 6 months (initially all four drugs followed by the former two drugs), constitutes the cornerstone treatment for pulmonary tuberculosis. Multi-drug resistant tuberculosis requires alternative chemotherapy, ideally in the form of individualised regimens, for management. To improve on the duration of chemotherapy for drug-susceptible tuberculosis and to achieve better treatment for multi-drug resistant tuberculosis as well as latent tuberculosis infection, there arises a genuine need for new drugs. The quest for new agents is, however, impeded by obstacles. Hopefully, tackling these through collaborative public-private partnerships on an international scale will lead to a fruitful outcome.     

Recent developments in the treatment of tuberculosis

The history of chemotherapy of tuberculosis commenced in 1944 with the discovery of streptomycin. Currently, short-course chemotherapy comprising rifampicin, isoniazid, pyrazinamide and ethambutol/streptomycin administered under directly observed settings for 6 months (initially all four drugs followed by the former two drugs), constitutes the cornerstone treatment for pulmonary tuberculosis. Multi-drug resistant tuberculosis requires alternative chemotherapy, ideally in the form of individualised regimens, for management. To improve on the duration of chemotherapy for drug-susceptible tuberculosis and to achieve better treatment for multi-drug resistant tuberculosis as well as latent tuberculosis infection, there arises a genuine need for new drugs. The quest for new agents is, however, impeded by obstacles. Hopefully, tackling these through collaborative public-private partnerships on an international scale will lead to a fruitful outcome.     

Combating Tuberculosis Infection: A Forbidding Challenge

After 50 years drought, several drugs are looming from the pipeline to combat tuberculosis. They will serve as a boon to the field that has been burdened with primitive, inadequate treatments and drug-resistant bacterial strains. From the decades, due to lack of interest and resources, the field has suffered a lot. Learning from the flaws, scientists have renovated their approaches to the finding of new antitubercular drugs. The first line drugs take about six months or more for the entire treatment. The second line remedy for resistant-tuberculosis requires daily injections which carry severe side effects. Drug resistance remains a constant menace because patients stop the medication once they start feeling better. So new drugs are required to be explored which are effective against tuberculosis especially drug resistant tuberculosis. These drugs need to work well with other drugs as well as with antivirals used for the treatment of human immunodeficiency virus. It is also very important to be considered that the treatments need to be cheap, as tuberculosis primarily affects people more in the developing countries. Further, new drugs must cure the disease in short span of time than the current six to nine month regimen. Recently a few new and potent drugs such as bedaquiline, delamanid, teixobactin have been evolved which may serve as a nice step forward, with a better outcome. Teixobactin, a new antibiotic has been found to have promising action against resistant strains, is also under consideration.     

Review article: the diagnosis and management of Crohn's disease in populations with high-risk rates for tuberculosis

BACKGROUND: Distinguishing Crohn's disease from intestinal tuberculosis in endemic areas is challenging as both conditions have overlapping clinical, radiological, endoscopic and histological characteristics. Furthermore, high rates of latent tuberculosis confer a considerable risk of reactivation once therapy for established Crohn's disease is started. AIM: To review current strategies in differentiating these two conditions, and in managing Crohn's disease, in populations with high rates of tuberculosis. METHODS: Literature review and clinical experience. RESULTS: While various clinical, radiological, endoscopic and histological parameters may aid in differentiating Crohn's disease from intestinal tuberculosis, these remain imperfect and as treatment options differ misdiagnosis has grave consequences. We propose a diagnostic algorithm, based on currently available evidence and experience, to aid in this dilemma. We also discuss approaches to the management of Crohn's disease, including agents targeting tumour necrosis factor-alpha, in patients at risk of developing tuberculosis. CONCLUSIONS: A diagnosis of Crohn's disease in individuals at risk for tuberculosis should only be made after careful interpretation of clinical signs, abdominal imaging and systematic endoscopic and histological assessment. Newer techniques for the diagnosis of latent tuberculosis still need to be validated in this environment, and guidelines on the treatment of latent tuberculosis in this setting require clarification.