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In India, Tuberculosis becomes a major public-health problem having the maximum number of incident and multidrug-resistant TB cases. Chemotherapy of Current tuberculosis is based on a combination of various drugs that was developed generally in the central decades of the previous century. Drug sensitive strains of Mycobacterium tuberculosis (M. TB) shows high cure rates, When the recommended compound and lengthy treatment protocols are adhered to. In this article the various TB tests are used to predict the severity of disease. This article highlights problems related to the optimized use of existing potent drugs and challenges related to the development of novel, potent and improved products, focusing on inherent in TB drug clinical development.
Keywords: - Tuberculosis drug development, Fluoroquinolones, test for TB, MDR-TB, XDR-TB etc
Tuberculosis (TB) has been well-known to us since ancient times. Generally it was called "consumption" in the first half of the 20th century. It is serious illness. In that time, majority of deaths is due to the tuberculosis because it is one of the major infectious diseases among all the infectious diseases. For the excellent control on TB, WHO introduced special hospitals, called sanatoriums, were used to control the spread of TB along with housing, better nutrition, and sanitation with use of potent antibiotics in the middle of the 20th century. Due to that TB and other infectious diseases became less extensive, preventable and curable. 1
Tuberculosis is an infectious airborne disease caused due to the bacterium Mycobacterium tuberculosis that typically affects the lungs, it also affects on the other organs and tissues such as the kidney, spine and brain can affect also, but in these parts of the body TB is usually not infectious. 2
As TB can affect organ systems other than the lungs, doctors practicing in various specialties may sometimes need to manage patients with this disease. This is an update of the previous consensus statement on chemotherapy of TB published in 1998. 3
Symptoms of Pulmonary TB disease
(TB disease usually causes one or more of the symptoms)
Symptoms of Extra pulmonary TB disease
(Depends on the part of the body that is affected by the disease)
Cough (particularly if lasting for 3 weeks or longer duration) with or without sputum production
Coughing up blood (hemoptysis)
Loss of appetite
Unexplained weight loss
TB of the kidney may cause blood in the urine
TB meningitis may cause headache or confusion
TB of the spine may cause back pain
TB of the larynx can cause hoarseness
Loss of appetite
Unexplained weight loss
It is desirable for TB patients to be managed by or in consultation with doctors experienced in this field. Proper pretreatment assessment and careful monitoring during treatment are necessary. While a treatment protocol is mandatory for programme purpose, flexibility as tailored to individual patient's clinical status is often needed. Drug adherence is crucial for treatment success and prevention of drug resistance. As far as possible, all Antituberculosis drugs should be administered using "directly observed treatment" to meet the purpose. All cases of TB must be notified to the Department of Health using notification form DH1A(s) Four drugs - isoniazid, rifampicin, Pyrazinamide, and either Ethambutol or streptomycin - are recommended for the initial 2-month phase of treatment.4-5
From the last 5000 years it is a well-known bacterial disease, which still infecting nearly one-third of World population with a day by day addition of 5000 new cases and loss of two lives every third minute. Every year in India, 1.9 million new cases are reported. Out of that 0.8 millions are 'Infectious smear positive TB cases'. As per WHO, in India death rate due to TB is nearly 28% per 1, 00,000 population, which is to be consider as the highest death rate among all other contagious diseases and accounts for 26 per cent of all preventable adult deaths .6
Symptoms of Tuberculosis 7
The symptoms of TB divided into two categories Pulmonary Symptoms and Extra pulmonary Symptoms
Cause of Tuberculosis 8
The infection of tuberculosis can develop after inhaling the droplets spread into the air from cough or sneeze by infected person. The main site of tuberculosis infection is the lungs, but other important organs also be involved. At the site of infection small area developed, called granulomas in the lungs. In the small number of infected people disseminated disease develops whose immune systems do not successfully contain the primary infection. Disseminated disease can occur within weeks after the primary infection, or may lie dormant for years before causing illness. Tuberculosis infection develops faster in infants, elderly person and those who have HIV/AIDS disease, because all they have weaker immune system. Organs and tissues affected in disseminated disease, can include
Cervical lymph nodes
Larynx (voice box)
Bones and joints
Lining of the spinal cord (meninges) and brain
Lining of the abdominal cavity (peritoneum)
Lining of the heart (pericardium)
Organs of the male or female urinary and reproductive systems
The risk of catching TB increases when you are in contact with people who have the disease, if you live in crowded or unsanitary conditions, and if you have poor nutrition.
Types of tuberculosis 8
Tuberculosis (TB) is divided into two categories, pulmonary and extra pulmonary.
Primary Tuberculosis Pneumonia
Extra pulmonary Tuberculosis
This type of tuberculosis occurs primarily in immune compromised patients.
Lymph Node Disease
Classification of Antitubercular agent
WHO Recommended Standard TB chemotherapy
Which includes two months of intensive, directly observed therapy (DOT), In Which They Categorised in two classes?
First line drugs (four)
second line drugs
In first line drugs, isoniazid and rifampicin follows minimum of 4 months of Treatement, Due to resistant of MDR-TB to both isoniazid and rifampicin, further it requires a two years of treatment with second-line drugs. 9
Extensive drug therapy(XDR-TB) arose from MDR-strains with acquired resistance to amino glycosides and FQs and, more recently, new forms of resistant bacilli have appeared that are totally drug-resistant or super extensive drug resistant. 10-11
2) On the basis of mechanism of action
It may be classified as follows:
Cell wall synthesis e.g. Ethionamide, isoniazid, cycloserine, Ethambutol
Bacterial protein synthesis e.g. amino glycosides
Nucleic acid synthesis e.g. quinolones, rifampin and
Electron transport across the bacterial membrane e.g. Pyrazinamide
Test for M. tuberculosis Infection 12
Choice of the most suitable tests for detection of M. tuberculosis infection should be based on the reasons and test availability, the context for testing, and overall cost effectiveness of testing. There are three tests currently available for the detection of M. tuberculosis infection in the United States.
These tests are
QuantiFERON-TB Gold in-Tube test (QFT-GIT)
Mantoux tuberculin skin test (TST) and Interferon-gamma release assays (IGRAs)
Tuberculin Skin test (TST) 13
This is the standard test for diagnosis of tuberculosis infection. The test includes the use of sterilized and concentrated extract from a tubercle bacilli culture filtrate. Now days the PPD (purified protein derivative) antigen used in the tuberculin which contain proteins that is common to Mycobacterium tuberculosis. Intradermal is most common technique for TST known as Mantoux technique. The test includes the intradermal injection on the ventral forearm of 0.1mL of PPD, a dose of 2UT. The reading is performed after 48-72h, but may be valid within 7 days.
Treatement on Tuberculosis
Principles of combination chemotherapy were helpful in the treatment of the TB. Multiple drug therapy now used to get more efficient treatment against mycobacterium tuberculi and to protect from resistance. 14
Tuberculosis (TB) becomes a chief global health concern whose control has been exacerbated by HIV and extensively drug-resistant (XDR-TB) strains of Mycobacterium tuberculosis and the emergence of multidrug-resistant (MDR-TB).The need for new, effective and faster acting TB drugs is increased today. The approaches like target based and cell based used today in development of an anti-TB drugs.In this articles, we describe the most capable anti-tubercular drug candidates that are in clinical development and launch those nitro-aromatic compounds that inhibit a new target, DprE1. DprE1 is an essential enzyme that involved in a fundamental step in mycobacterial cell wall biosynthesis. 15
Abbreviations: - MDR-TB (multidrug resistant TB), XDR-TB (extensively drug- resistant tb)
Fluoroquinolone in the management of Tuberculosis 16
Fluoroquinolone shows excellent activity against mycobacterium tuberculosis in vitro and in mouse models. They are the recent agents introduced in the treatment of tuberculosis. Because of their many characteristics, they became ideal antimycobacterial agents and show unique mechanism of action and no cross-resistance or antagonism with other antimycobacterial drugs. After administration they exhibit better oral bioavailability and required once daily dosing only. Its anti-TB activity due to the addition of methoxyl group at the C8 Position and is found in gatifloxacin, moxifloxacin and new FQ DC-159a. Some other FQs with good anti-TB activity include ciprofloxacin, sparfloxacin, ofloxacin, levofloxacin, sitafloxacin and clinafloxacin. Possible Sites of Action for the available anti-tuberculosis agents 17
J:\TB\Challenges Associated with Current and Future TB Treatment02 copy.jpgdfdf.jpg
Fig: - Schematic illustration of the site of action for the available anti-tuberculosis agents
Status of current tuberculosis drug therapy
For the treatment of tuberculosis available Drugs can be categorized into two classes. One is first line drugs such as, Ethambutol (EMB), Pyrazinamide (PZA), isoniazid (INH), rifampin (RIF), etc. and other is second line drugs like para amino salicylate (PAS), amikacin, cycloserine (CS), kanamycin, Ethionamide (ETA), thiacetazone, capreomycin, fluoroquinolones etc. Current TB therapy, also known as DOTS (directly observed treatment, short-course) consists of an initial phase of treatment with 4 drugs, INH, RIF, PZA and EMB, for 2 months daily, followed by treatment with INH and RIF for another 4 months, three times a week. 18
The targets of these drugs are various. INH is a cell wall component that inhibits synthesis of mycolic acid. 19
PZA targets cell membrane whereas rifampin and streptomycin interferes with the initiation and streptomycin interferes with the initiation of RNA and protein synthesis respectively. 20
EMB a major polysaccharide present in the mycobacterial cell wall blocks biosynthesis of arabinogalactan, while kanamycin and capreomycin, like streptomycin, inhibit protein synthesis through modification of ribosomal structures at the 16S rRNA. 21 Cycloserine which is a constituent of cell wall prevents the synthesis of peptidoglycan.22
Limitations of current drug therapy and need for new drug targets
In the present situation, DOTS is becoming rapidly ineffective in controlling tuberculosis because of the emergence of multi drug resistant tuberculosis (MDR-TB) and association between HIV and TB. Recent reports show that, DOTS is failing to control the disease in those areas where MDR-TB has high incidence.23
In such conditions, the second line drugs are preferred in combination with DOTS for TB Treatement. But, this combination of drugs is very expensive, because it has to be administered for a longer duration and has significant side effects. One chief drawback of current TB therapy is that the drugs are administered for at least 6 months. The patient compliance becomes difficult because of length of therapy, and due to this patients become potent source of drug-resistant strains. The second major and severe problem of current therapy is that most of the TB drugs available today are ineffective against persistent bacilli, except for PZA and RIF. RIF shows activity against both slow metabolizing non-growing bacilli and actively growing bacilli, while PZA shows activity against semi-dormant non-growing bacilli.24
However, there are still persistent bacterial populations that are not killed by any of the available TB drugs. Hence, there is a need to design new drugs which are most active against non-growing persistent bacilli or slowly growing bacilli to treat the population at risk of developing active disease through reactivation. Secondly, to encourage patient's Compliance and to slow down the development of drug resistance in mycobacterium, it is essential to achieve a shortened therapy schedule
RNTCP (REVISED NATIONAL TUBERCULOSIS CONTROLLING PROGRAM) 25
RNTCP or the Revised National Tuberculosis Control Program is the state run tuberculosis control program of the Government of India. It recommended the principles of directly observed treatment-short course (DOTS) which is the global TB control strategy of the World Health Organization. This program provides good quality and potent anti-tubercular drugs with free of cost, across the country through the growing number of private-sector DOTS-providers and the numerous Primary Health Centers. The DOT is a part of RNTCP and it follows five principle components.
DIRECTELY OBSERVED TREATEMENT, SHORT-COURSE THERAPY
DOTS- a five point strategy
Diagnosis by microscopy
Directly observed treatment
Adequate supply of Short Course drugs
Need of DOT in treatment of tuberculosis
It ensures that patients receive
The right Active drugs
In the Right doses
For the right duration of treatment
Major Activities under RNTCP
Treatment of TB patients
Surveillance and Monitoring
Advocacy, Communication and Social Mobilization (ACSM)
TB/HIV collaborative activities
DOTS-Plus for management of MDR-TB
Docking Software's used in the Development of Antitubercular Drugs 26-28
HEX 5.1 Software - for the designed compounds tried to dock with antitubercular protein from protein Data base (PDB).
Generate 3-D view (SDF format), convert it into MOL file.
Download PDB FILE (text) and save in Example Folder of Hex 5.1
Identify a target protein 2 YES from the Protein data Bank.
Draw all the ligands using Chem Sketch.
Convert into PDB format by using Swiss PDB viewer and save it.
Open Hex 5.1 software, select appropriate protein and ligand and perform Docking.
Tabulation the all ligands docking score PubChem software.
Quasar and Virtual ToxLab software
Marwin sketch software
New model for development of drug combination therapy for Tuberculosis
ADME --Absorption, distribution, metabolism and excretion
DDI -- Drug-drug interaction
DS -- Drug- Susceptible
EBA -- Early bactericidal activity
HRZE - Isoniazid, rifampicin, Pyrazinamide and Ethambutol
MAD - Multiple ascending doses
MDR - Multidrug- resistant
SAD - Single ascending dose
SSCC - Serial sputum colony count
Current Antibiotics for Treating Tuberculosis 29
Those people suffering from active cases of Tuberculosis, are firstly treated with four concurrent antibiotics namely Isoniazid, Rifampicin, Ethambutol, Pyrazinamide. Especially this treatment last for at least about six months. But can continue for up to two years and employ additional antibiotics if the invading bacteria are found to be drug-resistant. (Patient with latent tuberculosis is usually given just isoniazid alone for nine months). One or two of the ineffective medications will be replaced by second-line tuberculosis treatments. These include members of the following drug classes
Polypeptides (capreomycin, enviomycin, viomycin)
Amino glycosides (amikacin, kanamycin)
Thioamides (Ethionamide, prothionamide)
Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin)
Miscellaneous drugs (p-aminosalicylic acid, cycloserine)
New TB Molecules in Clinical development
Currently, a lot of drugs are in development for treatment of tuberculosis as compared to any period in the past 50 years having less potent drugs. For the first time several molecules appear on the horizon. Out of them ten compounds are in clinical development of which four are existing drugs redeveloped or repurposed for TB and remaining six are new chemical compounds particularly developed for tuberculosis.30
Following are the six newly developed compounds used in the Treatement of tuberculosis 31-32
(becomes most important second line drugs for treating MDR-TB)
DNA gyrase and DNA topoisomerase
C subunit of ATP synthase
Mycolic acid biosynthesis
50S ribosomal subunit
New Molecules or Compounds that are currently in preclinical or clinical development for the Treatement of Active tuberculosis 33
Discovery Preclinical Clinical development
Malate synthase InhA inhibitor MGI CPZEN-45 PNU-100480 Rifapentine Moxifloxacin
Protease Tryptanthrin Rimiphenazie TBK-613 Linezolid PA-824 Gatifloxacin
EM LeuRS inhibitor Nitroimidazole SQ641 SQ-109 TMC-207
RNA polymerase Menaquinone multifunctional SQ73 OPC-67683
Topol Summit comp. Dipiperidines SQ609
Phenotypic Kinase inhibitor Homopiperazines DC-159a
Natural product TL1 inhibitor AZD-4563
Focused screening BTZ-043
Future Strategy in treatment of tuberculosis 34
Strategic Vision 2006-2015
In 2015 the Working Group on New TB Drugs (WGND) envisions an environment that will allow for the sustained development of new TB drugs that can ultimately be combined into completely novel and innovative TB regimens. One of the lessons learned since the introduction of the existing anti-TB drugs is that continued worldwide commitment, research and attention to ensure a consistent pipeline of new antimicrobials will be required to destroy tuberculosis in the 21st century.
Particularly, the WGND's vision is to introduce new TB regimens which will achieve cure in 1-2 months or less, compatible with antiretroviral drugs, be effective against MDR-TB, effective against latent TB infection and used for treating HIV/AIDS. In addition, new TB regimens must be inexpensive and easily managed in the field. It is predicted that the overall goal is ambitious, but it is imperative that we succeed if we are to change the face of future TB therapy. It is conceivable, should progress continue to be made in the basic understanding of Mycobacterium tuberculosis (M.tb) biology, that the course of therapy could be reduced even further, to 10-12 days before 2050, or that other advances in therapeutic or prophylactic options not available today may also greatly reduce TB incidence.
To achieve this vision, the WGND has identified the following areas of strategic importance
Basic discovery biology to identify and validate new targets and identify candidate compounds using effective screens and creative medicinal chemistry.
Clear and efficient regulatory guidance and
more effective clinical trial planning and execution, including identification of improved biomarkers and methods of assessing latent disease
This article shows the status of current TB (antibiotics) drugs and their resistance. First line drugs are more efficacious, safety and produce greater patience compliance than second line drugs. Second line drugs used only when resistance produced by first line drugs. Lengthy continuous treatment required for TB. XDR-TB is severe than MDR-TB to treat. Recently a lot of novel potent drugs are in clinical development.