Anti-Tuberculosis Drugs: An introduction, classification, mechanism, chemistry, with its uses.

Antituberculosis

anti-tuberculosis

Anti tuberculosis drugs are the drugs or agents which are used for the treatment of tuberculosis with the combination of the drugs. Tuberculosis (TB) is the most prevalent infectious disease worldwide and a leading killer caused by a single infectious agent, that is, Mycobacterium tuberculosis. Mycobacterium tuberculosis is as acid-fast aerobic bacillus. The bacteria of TB are usually attacking the lungs, but they can also damage other parts of the body.

History

According to the report of the World Health Organization (WHO), M. tuberculosis currently infects over 2 billion peoples worldwide, and 30 million new cases reported every year.  This intracellular infection accounts for at least 3 million deaths annually.

Remarkable progress has been made in the last 65 years since the introduction of Streptomycin in 1947 for the treatment of tuberculosis. Its full therapeutic potential could be utilized only after 1952 when isoniazid was produced to accompany it.

The discovery of ethambutol in 1961, rifampin in 1962, and redefinition of the role of pyrazinamide have changed the strategies in the chemotherapy of tuberculosis. Since 1970 efficacy of short-course (6–9 months) and domiciliary regimens has been demonstrated and clear-cut treatment guidelines have been formulated.

Symptoms of tuberculosis-

TB is spread through the air, a person with TB can spread it from person to person by throat coughs, sneezes, or talks, etc. General symptoms associated with Tb are a cough that lasts more than 3 weeks, chest pain, coughing up blood, feeling tired all the time, night sweats, chills, and fever, loss of appetite, and weight loss.

M. tuberculosis is able to reproduce inside the macrophage and ultimately kill the immune cell. The main site of infection is in the lungs. Tuberculosis of the lungs may also occur through infection from the bloodstream.

This transmission can also spread the infection to more far-off sites like peripheral lymph nodes, the kidney, the brain, and the bones. All parts of the body can be affected by this disease and it rarely affects the heart, skeletal muscles, pancreas, or thyroid.

You may read- treatment of tuberculosis.

Tuberculosis has two types-

Latent tuberculosis- In latent TB the presence of germs in your body, but the immune system stops them from spreading. That means there is no symptom and the person is not contagious. The infection is still alive in the body and becomes active.

These are generally treated with isoniazid alone or in combination with either rifampicin or rifapentine. The treatment time is at least three months. People with latent infection are treated to prevent them from becoming active TB diseases.

Active tuberculosis- In-active TB the germs are multiplied and can make sick. A person can spread the disease to another person. Most cases of active TB are from the reactivation of a latent TB infection.

Active TB diseases are best managed with a combination of several antibiotics to reduce the risk of the bacteria developing antibiotic resistance. Anti-tubercular drugs are classified into two types-

Classification of anti tuberculosis –

First-line drugsSecond-line drugsFluoroquinolones
IsoniazidEthionamideLevofloxacin
RifampinProthionamideMoxifloxacin
PyrazinamideCycloserineCiprofloxacin
EthambutolTerizidoneInjectable drugs
StreptomycinPara-amino salicylic acid (PAS)Kanamycin
ThiacetazoneAmikacin
Capreomycin

First-line drugs

The first line of drugs often fails to cure TB for various reasons. Relapse and the spread of the diseases contribute to the development of drug-resistant bacteria which is resistant to isoniazid and rifampicin.

Because of this, there is a need for second-line drugs that are difficult to procure. The first-line drugs are having high antitubercular efficiency as well as a low toxicity, and these are used routinely.

Mechanism-of-first-line-drug

Isoniazid

Isoniazid is a highly effective and most widely used antitubercular drug. It is orally effective, cheapest, and has tuberculocidal activity. It is active against both intracellular and extracellular bacilli.

It is the first-line drug for the treatment of tuberculosis. It inhibits the biosynthesis of mycolic acids, which are essential constituents of the mycobacterial cell wall. It is readily absorbed from the gut, and distributed well all over the body.

Mechanism of action-

Isoniazid is a prodrug that is activated on the surface of M. tuberculosis by katG enzyme to isonicotinic acid. Isonicotinic acid inhibits the bacterial cell wall mycolic acid, thereby making M. tuberculosis susceptible to reactive oxygen radicals.

It may be bacteriostatic or bactericidal in the action, and it is depending on the concentration of the drug that attained at the site of infection and the susceptibility of the infecting organism. It is active against the susceptible bacteria only during bacterial cell division.

Isoniazid (Prodrug)

                            ↓       inside mycobacteria

Converted to the active form

Inhibits the mycolic acid synthesis (A component of the mycobacterial cell wall)

Death of bacteria (Tuberculocidal)

Molecular formula– C6H7N3O
Molecular weight– 137.1g/mol
IUPAC Name– pyridine-4-carbohydrazide
Structure of isoniazid-
Structure-of-isoniazid
Preparation of isoniazid-
Preparation-of-isoniazid
Properties

It is a white crystalline powder or colorless crystals.

It is odorless but slightly sweet at first and the bitter in taste.

It is soluble in water and sparingly soluble in alcohol.

 It is practically insoluble in ether and benzene.

It gets metabolized in the liver by acetylation.

Uses

Used as an anti tuberculosis drug.

Used in the treatment of latent and active tuberculosis infections.

Used for chemoprophylaxis of tuberculosis.

Used in the treatment of Mycobacterium avium complex.

Rifampin

The major metabolism of rifampin is deacetylation, which occurs at the C-25 acetate.  The resulting products, desacetyl rifampin, and desacetyl rifapentine are still active antibacterial agents.  3-Formylrifamycin has been reported as a second metabolite following both rifampicin and rifapentine administration.

Mechanism of action-

It is an antibiotic obtained from Streptomyces Mediterranean. It inhibits the DNA-dependent RNA polymerase of mycobacteria by forming a stable drug enzyme complex, which is leading to suppression of initiation of chain formation in RNA synthesis and acts as a bactericidal drug.

Molecular formula– C43H58 N4O12
Molecular weight– 822.9g/mol
IUPAC Name– [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(E)-(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate
Structure of rifampin-
Structure-of-rifampin
Properties

It is a reddish-brown or brownish-red crystalline powder.

It is slightly soluble in water, acetone, alcohol, and soluble in methanol.

It is the most active agent in clinical use for the treatment of tuberculosis.

Uses

Used only in combination with other antitubercular drugs, and it is ordinarily not recommended for the treatment of other bacterial infections when alternative antibacterial agents are available.

Used as anti tuberculosis agent.

Pyrazinamide

Pyrazinamide is a prodrug and it is activated by M. tuberculosis amidase enzyme into pyrazine carboxylic acid, which has bactericidal activity. It is a synthetic analog of nicotinamide. It is active in acidic pH and effective against intracellular bacilli, also has sterilizing activity. It is given orally and absorbed well from the GI tract and distributed widely throughout the body including the CSF. This drug is metabolized in the liver and then excreted from the urine.

Mechanism of action-

It interferes with the bacterial ability to synthesize new fatty acids required for growth and replication of bacteria. It gets converted into pyrazinoic acid which inhibits the enzyme fatty acid synthase -I, which is required by the bacterium to synthesize fatty acids.

Molecular formula-C5H5 N3O
Molecular weight– 123.11g/mol
IUPAC Name– pyrazine-2-carboxamide
Structure of pyrazinamide-
Structure-of-pyrazinamide
Properties-

It is a white crystalline powder.

It is sparingly soluble in water, slightly soluble in alcohol and in methylene chloride.

It has recently been elevated to the first-line status in the short-term treatment of tuberculosis regimens because of its tuberculocidal activity and comparatively less short-term toxicity.

It is maximally effective in the low pH environment that exists in macrophages (monocytes).

Uses

Used to treat tuberculosis as anti tuberculosis agent and meningitis.

Used with great caution in patients with hyperuricemia or gout.

Ethambutol

Ethambutol is a first-line anti tuberculosis drug. It is a bacteriostatic drug and specific for mycobacteria. It is well absorbed after oral administration, distributed widely in the body and metabolized in the liver, crosses the blood-brain barrier in meningitis, and excreted in the urine. It should avoid in children below 6 years age because they may not be able to report the disturbances in vision.

Mechanism of action-

Ethambutol is interfering with the biosynthesis of arabinogalactan which is a major polysaccharide of the mycobacterial cell wall. It inhibits the polymerization of the cell walls and results in blockage of bacterial growth. It also inhibits RNA synthesis and decreases replication to tubercle bacilli. It is a bacteriostatic drug that inhibits the incorporation of mycolic acid into the mycobacterium cell wall.

Molecular formula– C10H24N2O2
Molecular weight– 204.31g/mol
IUPAC Name– (2S)-2-[2-[[(2S)-1-hydroxybutan-2-yl] amino] ethyl amino] butan-1-ol
Structure of ethambutol-
Structure-of-ethambutol

Properties

It is a white crystalline powder, odorless and bitter in taste.

It is soluble in water and alcohol.

It is not recommended for use as a single drug but used in combinations with other antitubercular drugs in the chemotherapy of pulmonary tuberculosis.

It gets metabolized in the liver mainly by oxidation.

Uses

It is an antibiotic that has bacteriostatic, antimicrobial, and antitubercular properties with anti tuberculosis agent.

Streptomycin

Streptomycin is the first effective drug which is used for the treatment of tuberculosis. It is a bactericidal drug. It is not effective orally, so it must be injected intramuscularly.  It is most often used in combination with other drugs, such as ethambutol and isoniazid, to treat pulmonary infections in patients with organisms that are known to be resistant. There has been an increasing tendency to reserve streptomycin products for the treatment of tuberculosis.

Mechanism of action-

Streptomycin binds to the bacterial 30S ribosomal subunit and causes misreading of t-RNA; hence the bacterium becomes unable to synthesize proteins essential for its growth.

Molecular formula- C21H39N7O12
Molecular weight- 281.6g/mol
IUPAC Name– 2-[(1R,2R,3S,4R,5R,6S)-3-(diaminomethylideneamino)-4-[(2R,3R,4R,5S)-3-[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine
Structure of streptomycin-
Structure-of-streptomycin

Properties

Streptomycin is a white hygroscopic powder, odorless, and slightly bitter in taste.

It is very soluble in water and practically insoluble in ethanol, chloroform, and ether.

It is active against extracellular bacilli in alkaline pH.

Its solution is levorotatort.

It is not metabolized and gets execrated unchanged in the urine mainly by glomerular filtration.

Uses

Used as antibacterial and tuberculostatic.

Used as fungicide and in seed treatment.

Used in combination with penicillin, as an antibiotic to prevent bacterial infection during cell culture.

second-line drugs

 The second-line drugs having either low antitubercular efficacy or higher toxicity. These are less effective and less well tolerated anti-TB drugs that are used only in case of the bacilli are resistant to one or more first-line drugs or when these are not tolerated and are contraindicated.

Ethionamide

It is structurally similar to isoniazid but it is less efficacious. It is a bacteriostatic drug and it is effective against both extracellular and intracellular bacilli. It is well absorbed after oral administration, and distributed widely all over the body including the CSF.

Mechanism of action-

It inhibits the synthesis of mycolic acid found in the bacterial cell wall, thereby inhibiting bacterial cell wall synthesis. It leads to bacterial cell wall disruption and causes cell lysis. The antimycobacterial action of ethionamide seems to be due to an inhibitory effect on mycolic acid synthesis.

Molecular formula– C8 H10N2S
Molecular weight– 166.25g/mol
IUPAC Name– 2-ethylpyridine-4-carbothioamide 
Structure of ethionamide-
Structure-of-ethionamide

Properties-

Ethionamide is yellow crystalline powder or crystals with a faint to moderate sulfoxide odor.

It is practically insoluble in water, soluble in methanol, and sparingly soluble in alcohol.

It gets metabolized in the liver to give active metabolite sulfoxide and several inactive metabolites.

The sulfoxide metabolite has antimicrobial activity against Mycobacterium tuberculosis.

Uses-

Used as an anti tuberculosis agent.

Used in combination with other antitubercular drugs, as a part of a second-line regimen for the treatment of tuberculosis.

Used in the treatment of Mycobacterium avium complex.

Prothionamide

Prothionamide is a close congener of ethionamide, to which it resembles in antimycobacterial property, mechanism of action, pharmacokinetics, and adverse effects. Clinically it is considered interchangeable with ethionamide for use in MDR-TB, MAC infection, etc.

Molecular formula– C9 H12N2S
Molecular weight- 180.27g/mol
IUPAC Name– 2-propylpyridine-4-carbothioamide 
Structure of prothionamide-
Structure-of-prothionamide

Cycloserine

Cycloserine is an orally effective, tuberculostatic drug that disrupts D-alanine incorporation into the bacterial cell wall. Cycloserine distributes well throughout body fluids, which including in the CSF. Cycloserine is primarily excreted unchanged in the urine. Accumulation occurs with renal insufficiency. Adverse effects involve CNS disturbances for example- lethargy, difficulty concentrating, anxiety, and suicidal tendency, and seizures may occur.

Mechanism of action-

Cycloserine is causing interference in the bacterial cell wall synthesis in the cytoplasm by competitively inhibiting two enzymes, L-alanine racemase, these are forms D-alanine into the pentapeptide which is required for peptidoglycan formation and bacterial cell wall synthesis.

Molecular formula-C3H6N2O2
Molecular weight- 102.09g/mol
IUPAC Name- (4R)-4-amino-1,2-oxazolidin-3-one
Structure of cycloserine-
Structure-of-cycloserine

Properties-

It is a white to pale yellow crystalline solid powder which is odorless or faint odor.

It is soluble in water and slightly soluble in methanol, propylene glycol.

It forms salts with acids and bases.

Uses-

Used in combination with other antitubercular drugs in the treatment of tuberculosis when primary drugs do not work.

Used as an anti-infective agent, an antibiotic, and antimetabolite.

Used to treat mycobacterium avium complex.

Pare-amino salicylic acid

Para-amino salicylic acid (PAS) works via folic acid inhibition. While it is largely replaced by ethambutol for the drug-susceptible TB, then PAS remains an important component of many regimens for MDR-TB. It is bacteriostatic and highly specific for M. tuberculosis. Side effects are anorexia, nausea, epigastric pain, diarrhea, and making poor compliance.

Mechanism of action-

Aminosalicylic acid is an inhibitor of bacterial folate metabolism in a manner similar to the sulfonamide antibacterial. It is an analog of para-aminobenzoic acid (PABA) with antitubercular activity. Aminosalicylic acid produces its bacteriostatic activity against Mycobacterium by competing with PABA for the enzyme which is involved in folate synthesis. It inhibits folic acid synthesis and thereby stops the growth and reproduction of M. tuberculosis and causes cell death. It also inhibits the synthesis of cell wall component mycobactin.

Molecular formula- C7H7NO3
Molecular weight- 153.14g/mol
IUPAC Name- 4-amino-2-hydroxybenzoic acid
Structure of action-
Structure-of-para-amino-salyclic-acid

Properties

It is a white crystalline powder and has a slight acetous odor.

It is soluble in water, dilute nitric acid and dilute sodium hydroxide.

It is insoluble in benzene, chloroform, or carbon tetrachloride.

It gets metabolized in the liver.

Uses-

Used as anti tuberculosis agent.

Rifabutin

Rifabutin is a derivative of rifampin, is preferred for TB patients coinfected with the human immunodeficiency virus (HIV) who are receiving protease inhibitors or several of the nonnucleoside reverse transcriptase inhibitors. It is a less potent inducer (approximately 40% less) of cytochrome P450 enzymes, thus lessening drug interactions. Its adverse effects are similar to those of rifampin but can also cause uveitis, skin hyperpigmentation, and neutropenia.

Mechanism of action-

It causes the inhibition of DNA-dependent RNA polymerase in both gram-positive and some gram-negative bacteria and that leads to suppression of RNA synthesis and cell death.

Molecular formula- C46H62N4O11
Molecular weight- 847g/mol
IUPAC Name- [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1′-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4′-piperidine]-13-yl] acetate 
Structure of rifabutin-
Structure-of-rifabutin

Properties

Rifabutin is a violet-red crystalline powder.

It is highly soluble in chloroform, and soluble in methanol, slightly soluble in ethanol, less soluble in water.

It is metabolized in the liver.

Uses

Used in an antibacterial and tuberculostatic.

Used to treat AIDS patients having Mycobacterium infection and inhibit replication of human immunodeficiency virus type 1 (HIV- 1).

Thiacetazone

Its efficacy in TB is now considered uncertain, and it is not indicated, even as a reserve drug, in MDR-TB.

Molecular formula- C10 H12N4OS
Molecular weight-236.3g/mol
IUPAC Name- N-[4-[(E)- (carbamothioyl hydrazinylidene) methyl] phenyl] acetamide  
Structure of thiacetazone-
Structure-of-Thiacetazone

Uses

Used as anti tuberculosis agent.

You may read- antimicrobial agents.

Fluoroquinolones

Fluoroquinolones like ofloxacin, levofloxacin, ciprofloxacin, and moxifloxacin are relatively new potent oral bactericidal drugs for TB, that have gained prominence as well as tolerated alternatives to first-line anti-TB drugs.

They are active against MAC, M. fortuitum, and some other atypical mycobacteria, as well as moxifloxacin, which is the most active Fluoroquinolones against M. Tuberculosis, while levofloxacin is more active than ofloxacin and ciprofloxacin.

Fluoroquinolones are a key component of all regimens for MDR-TB, except when bacilli are found to be resistant to them. The RNTCP has included ofloxacin/levofloxacin in the standardized regimen for MDR-TB.

If used alone, mycobacterial resistance to ofloxacin, levofloxacin, and ciprofloxacin develops rapidly by mutation of the DNA gyrase gene. Interestingly, experimental data indicate that resistance against moxifloxacin is slow to develop.

Structure of fluroquinolones-
Structure-of-levofloxacin
Levofloxacin
Structure-of-moxifloxacin
moxifloxacin
Structure-of-ciprofloxacin
Ciprofloxacin

Injectable drugs

Amikacin

Amikacin is a semisynthetic derivative of kanamycin to which it resembles in pharmacokinetics, dose, and toxicity. In amikacin, the outstanding feature is its resistance to bacterial aminoglycoside inactivating enzymes. Hereby, amikacin has the widest spectrum of activity, which including in many organisms resistant to other aminoglycosides.

Structure of amikacin-
Structure-of-amikacin

Uses

Used as anti tuberculosis agent.

Kanamycin

Kanamycin was obtained from S. kanamyceticus in the year 1957, and it was the second systemically used aminoglycoside to be developed after streptomycin. Kanamycin is similar to streptomycin in all respects including efficacy against M. tuberculosis and lack of activity on Pseudomonas. However, it is more toxic, both to the cochlea and to the kidney. Hearing loss, which is irreversible, is more common than vestibular disturbance.

Structure of kanamycin-
Structure-of-kanamycin

Capreomycin

It is a cyclic peptide antibiotic, which is chemically very different from aminoglycosides, but with similar mycobactericidal activity, ototoxicity, and nephrotoxicity. In addition, it often causes eosinophilia, rashes, fever, and injection site pain. It has to be injected intramuscularly. Many M. tuberculosis isolates resistant to streptomycin and Amikacin, as well as MDR-TB remain susceptible to it.

Mechanism of action-

This is a parenterally administered polypeptide that inhibits protein synthesis by binding to the 30S ribosomal unit similar to aminoglycosides. It also binds to the components in the bacterial cell which results in the production of abnormal proteins. It is primarily reserved for the treatment of MDR-TB diseases. Careful monitoring of renal function and hearing is necessary to minimize nephrotoxicity and ototoxicity, respectively.

Molecular formula-C50H88N28O15
Molecular weight- 1321.4g/mol
IUPAC Name- (3S)-3,6-diamino-N-[[(2S,5S,8E,11S,15S)-15-amino-11-[(4R)-2-amino-1,4,5,6-tetrahydropyrimidin-4-yl]-8-[(carbamoylamino)methylidene]-2-(hydroxymethyl)-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide;(3S)-3,6-diamino-N-[[(2S,5S,8E,11S,15S)-15-amino-11-[(4R)-2-amino-1,4,5,6-tetrahydropyrimidin-4-yl]-8-[(carbamoylamino)methylidene]-2-methyl-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide
Structure of capreomycin-
Structure-of-capreomycin

Properties

It is a member of the antibiotics in the aminoglycoside family.

It has the ability to kill a wide variety of bacteria, including the bacteria which is responsible for causing tuberculosis (TB).

It is a white crystalline powder.

It is soluble in water as a disulfate salt.

It is metabolized in the liver.

Uses

Used only as an alternative to aminoglycoside antibiotics.

Used as antibacterial and tuberculostatic.

Used in combination with other antitubercular drugs in the treatment of tuberculosis when resistance to primary drugs occurs.

Bedaquiline

It is a diarylquinoline, and it is an ATP synthase inhibitor, which is approved for the treatment of MDR-TB. In general, it is administered orally, and it is active against many other types of mycobacteria.

Bedaquiline has a boxed warning for QT prolongation, and monitoring of the electrocardiogram is recommended. Elevations in liver enzymes have also been reported and liver function should be monitored during therapy. This agent is metabolized via CYP3A4, and administration with strong CYP3A4 inducers (for example, rifampin) should be avoided.

Molecular formula- C32H31BrN2O2
Molecular weight- 555.5g/mol
IUPAC Name- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-1-yl-1-phenylbutan-2-ol

Mechanism of action-

It is a diarylquinoline antimycobacterial drug that inhibits the proton pump of mycobacterial ATP synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis. Bacterial death occurs as a result of bedaquiline.

Structure of bedaquiline-
Structure-of-bedaquiline

Properties-

It is in white solid form to almost white powder.

It is practically insoluble in aqueous media.

It acts as also an antimicrobial drug that inhibits mycobacterial ATP synthase.

Uses

Used as an anti tuberculosis agent.

Used as a medication or supplement.


This Post Has 3 Comments

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