A Note on Derivatives of Isoniazid,Rifampicin, and Pyrazinamide Showing Activity Against Resistant Mycobacterium tuberculosis

Drug‐resistant tuberculosis (DR‐TB) is a serious problem that impedes the success of the TB control program. Of note, multidrug‐resistant (MDR)‐TB and extensively drug‐resistant (XDR)‐TB have certainly complicated the scenario. One of the possible strategies to overcome drug resistance in an economic and simple manner would involve modification of existing anti‐TB drugs to obtain derivatives that can work on resistant TB bacilli. These may have improved half‐life and increased bioavailability, be more efficacious, and serve as cost‐effective alternatives, as compared to new drugs identified through conventional methods of drug discovery and development. Although extensive literature is available on the activity of various derivatives of first‐line drugs (isoniazid, rifampicin and pyrazinamide) on drug‐susceptible Mycobacterium tuberculosis (MTB), reports on the activity of derivatives on resistant MTB are very limited, to our knowledge. In light of this, the present review aims to provide a concise report on the derivatives of first‐line drugs that have the potential to overcome the resistance to the parental drug and could thus serve as effective alternatives.     

Effective therapy with the neuroleptic thioridazine as an adjunct to second line of defence drugs, and the potential that thioridazine offers for new patents that cover a variety of "new uses"

New and active infections of tuberculosis continue to increase globally. Although antibiotic susceptible infections can be readily cured with isoniazide and rifampicin, infections resistant to these two antibiotics, named Multi-Drug Resistant TB (MDR TB), are problematic for therapy, extol high costs in terms of human suffering and finances, and when these MDR infections progress to Extensive Drug Resistant TB (XDR TB) status, they are not only difficult to treat, they produce high levels of mortality regardless of therapeutic modality employed. The neuroleptic thioridazine (TZ) has been shown to have wide spectrum in vitro and ex vivo activities against antibiotic susceptible, MDR and XDR strains, and has been successfully used for curing mice of active tuberculosis produced by antibiotic susceptible and MDR strains, and has cured 10 out of 12 XDR TB patients when used in combination with three antibiotics to which the XDR TB patients were non-responsive. Mycobacterium tuberculosis TZ has been recommended for "Compassionate Therapy" of MDR/XDR TB infections whose prognoses are significantly serious and anticipated to result in mortality. This review of TZ activity and its potential to cure MDR/XDR TB supports the contention that this neuroleptic offers patenting opportunities for "New Use". The motivation for patents therefore is expected to rapidly bring TZ to the forefront for therapy of MDR/XDR TB and therefore, the striving for new patents is expected to contribute to the prevention of new infections of antibiotic resistant tuberculosis.     

Emerging technologies for monitoring drug-resistant tuberculosis at the point-of-care

Infectious diseases are the leading cause of death worldwide. Among them, tuberculosis (TB) remains a major threat to public health, exacerbated by the emergence of multiple drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb). MDR-Mtb strains are resistant to first-line anti-TB drugs such as isoniazid and rifampicin; whereas XDR-Mtb strains are resistant to additional drugs including at least to any fluoroquinolone and one of the second-line anti-TB injectable drugs such as kanamycin, capreomycin, or amikacin. Clinically, these strains have significantly impacted the management of TB in high-incidence developing countries, where systemic surveillance of TB drug resistance is lacking. For effective management of TB on-site, early detection of drug resistance is critical to initiate treatment, to reduce mortality, and to thwart drug-resistant TB transmission. In this review, we discuss the diagnostic challenges to detect drug-resistant TB at the point-of-care (POC). Moreover, we present the latest advances in nano/microscale technologies that can potentially detect TB drug resistance to improve on-site patient care.     

Tb drug resistance: is it really a threat to Africa?

In most of the world and particularly in Eastern Europe, China and India, drug resistance is increasingly seen as a major threat to tuberculosis (TB) control and even to public health and health security. What about in Africa? The conditions for creation of drug resistance exist in most, if not all, African countries, as a result of underinvestment in basic TB control, poor management of anti-TB drugs and virtual absence of infection control measures. The severity of drug resistance is increasing--following outbreaks all over the world of multi-drug resistant TB (MDR) in the 1990's, extensive drug resistant (XDR) TB has now been found in 37 countries, including South Africa. (MDR is, in essence, resistance to the most powerful first-line drugs, and XDR-TB is TB resistant to the most powerful second-line drugs as well.) Worse still, the impact of XDR-TB is magnified among those with HIV infection, giving rise to a remarkably high mortality, and exposing significant weaknesses in both HIV and TB control. In particular, the lack of laboratories capable of carrying out culture and drug susceptibility testing severely limits the capacity of countries even to detect the problem in Africa. This paper analyses the threat of TB drug resistance to health and to TB control in Africa, and puts forward measures to diminish this threat.     

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.     

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。     

Drug-resistant and multidrug-resistant tubercle bacilli

Drug resistant (DR) and multidrug resistant (MDR) tuberculosis (TB) is a consequence of human activity and did not exist before chemotherapeutic drugs were introduced. Monotherapy with various drugs in sequence or other inadequate drug regimens have strongly contributed to the creation of MDR-TB. Such TB strains are mainly prevalent in regions with weak national TB programmes or poor socio-economic environments. Strains may also spread in some communities such as poorly administered prisons. From these and other sources, MDR-TB may spread in the population from which travellers might transfer strains between countries and continents. Therefore an effective surveillance of the resistance pattern of TB bacilli is a demanding task in all countries. In this review some aspects of epidemiology, diagnosis and mechanisms of DR in TB are discussed. MDR-TB is an important international problem of increasing significance for the whole global community.     

喹诺酮抗分枝杆菌活性及其构效关系研究进展

随着耐药结核病(尤其是耐多药结核病)发病率的不断上升以及结核病与AIDS病的并发,结核病疫情再度上升,成为全球重大公共卫生问题。作为二线抗结核病药物,氟喹诺酮类药物具有一定优势,它们在临床治疗耐多药结核病以及对不能耐受一线抗结核病药物的患者治疗中扮演着重要角色。本文综述了近年来喹诺酮(包括氟喹诺酮、6-非氟喹诺酮和非经典喹诺酮)在抗分枝杆菌活性及其构效关系方面的研究进展。     

我国结核病耐药状况及其变化趋势分析

目的:了解结核病总体耐药、初始耐药和获得性耐药状况及其变化趋势,为改进结核病防治措施提供参考。方法:对国内1995～2005年结核病耐药监测结果进行综合评价,应用SPSS软件进行统计学分析。结果:1995～2005年我国人群结核耐药趋势总体呈下降趋势,总耐药率为24．8％。在耐药病例中,初始耐药率为20．6％,获得性耐药率为44．3％,获得性耐药率显著高于初始耐药率。不同抗结核药物的耐药顺序为:初始耐药异烟肼(15．3％)>链霉素(10．6％)>利福平(8．1％)>乙胺丁醇(4．2％);获得性耐药异烟肼(35．1％)>利福平(26．1％)>链霉素(23．3％)>乙胺丁醇(11．3％)。耐多药率中,1～4种耐药率按年份均呈缓慢下降趋势。耐药率排序为:单药>2药>3药>4药,耐多药率显著高于耐单药率。结论:我国人群结核耐药趋势总体呈缓慢下降趋势,但与发达国家相比,仍属高耐药水平,面临的形势依然十分严峻。     

论临床结核病耐药性变化趋势的动态监测分析与研究

目的对临床结核病耐药性的变化趋势的动态监测的方法进行探讨。方法选择2008年至2011年经确诊的2000例肺结核患者作为研究对象,对其耐药菌株进行治疗前与治疗后的动态监测,并对药敏结果进行统计与分析,最终确定治疗前后耐药菌谱的变化情况。结果本组2000例肺结核患者的耐药均值在治疗前与治疗后对抗结核药物的耐单药例数是有一定差异的,以乙胺丁醇（Ethambutol,EMB）药物的耐药例数发生了较为明显的变化,耐药性显著增加,前后对比呈显著的统计学差异（P〈0．01）;对丁胺卡那霉素（Amikacin,AMK）、卷曲霉素（Capreomycin,CPM）以及对氨基水杨酸（Sodium Aminosalicylate,PAS）三种药物的初始耐药率及复敏率较高。结论对耐多药肺结核患者的耐药菌株进行动态监测,可以准确获取耐药菌株耐药性信息,具有重要的临床意义与价值;同时对目前使用EMB等药物治疗的方案提出警示与质疑,尽快地开发新一代的毒性低、效率高的抗结核药物是目前解决抗结核治疗困境的一个当务之急。     

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.     

结核菌耐药的基因及治疗

近年来．随着化疗药物的广泛应用。耐药结核病,尤其是耐多药结核病（MDR-TB）对全球结核病控制造成严重威协。高耐药率和耐多药菌株以及广泛耐药结核病的不断扩散,正日益成为全球结核病控制中的一个重大问题。而我国多耐药结核病疫情属全世界22个高负担国家之一。     

Mechanistic investigation of resistance via drug-inactivating enzymes in Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is a serious major health concern that has existed from millennia. According to annual WHO report 2016, it is considered as world’s ninth highest killer disease by single infectious agent, ranking above HIV/AIDS. To worsen the scenario the development of multi-drug resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB) have significantly reduced the success rate of TB treatment. Several efforts are being made to handle pharmacodynamic resistance (MDR and XDR-TB) involving designing of new inhibitors, targeting mutated target or by multi-targeting agents. However, the issue of pharmacokinetic resistance in TB is not being addressed appropriately till date. Pharmacokinetic mode of resistance involves an intrinsic mechanism of bacterial drug resistance via expression of various enzymes and efflux pumps that are responsible for the loss of activity of the therapeutic agents. Mycobacterium tuberculosis is also intrinsically resistant to various approved agents via pharmacokinetic mechanism of resistance. Several bacterial enzymes are encoded that either degrade or modifies the drugs and renders them ineffective. Targeting such inactivating bacterial enzymes provides a novel approach to make the current therapy effective and combat the problem of resistance. This review provides an insight into different bacterial enzymes which are responsible for pharmacokinetic drug resistance in TB. The structure attributes and mechanism of catalysis employed by these enzymes to inactivate drug have also been discussed which may provide basis for developing novel therapeutic agents for resistant TB.     

XDR-TB, what is it; how is it treated; and why is therapeutic failure so high?

Drug resistance is a major hurdle in the global battle against tuberculosis (TB). In tackling this problem it is important to understand both how resistance emerges as well as the ways in which multi-drug and extensively drug-resistant TB (M/XDR-TB) may be successfully treated. The biggest problem with treatment is the lack of effective drugs. Exciting developments have been made in this area over recent years with useful drugs being found from older agents as well as new discoveries. Patent applications are being made for novel agents and are also possible as new use for older agents such as thioridazine. A flourishing drug pipeline is critical if we are to make progress in the management of M/XDR-TB.     

陕西省秦巴项目地区结核菌耐药监测分析

目的：了解陕西秦巴地区结核菌耐药情况,为结核病控制提供科学依据、今后耐药监测提供经验。方法：采用《结核菌耐药性监测方案》规定的方法进行监测,对2005年10个项目县新登记的初、复治涂阳肺结核病例的痰标本进行分离培养和药敏试验。结果：共入选360例,培养阳性283例,其中结核分枝杆菌复合群273例,非结核分枝杆菌10例。总耐药率为28．9％,初始耐药率为24．6％,获得性耐药率为39．0％;耐多药率（MDR）为2．6％。结论：初始耐药率高于2000年全国流行病学调查结果,获得性耐药率低于2000年全国流行病学调查结果。提示应进一步扩大监测范围,加强病人的用药指导与治疗管理。     

Promising drugs against tuberculosis

Tuberculosis (TB) is an important public health problem worldwide due to AIDS epidemic, the advent of multidrug resistant strains (MDR) and the lack of new drugs in the market. TB is responsible for almost 3 millions deaths each year. According to WHO (World Health Organization), which declared tuberculosis a global health emergency in 1993, tuberculosis, without a coordinated control effort, will infect an estimated 1 billion people by 2020, killing 70 million. In spite of this problem, there is a lack of development of new TB drugs. For example, it has been nearly 35 years since the introduction of a new class of compounds for the treatment of TB. Thus, there is an urgent need for new drugs to fight against this disease. Considering that, this review aims promising drug candidates that are in development against TB.     

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.