**2. Etiology and routes of transmission**

Tuberculosis (TB) is caused by the *Mtb* complex. The mycobacterium is nonmotile, Gram-positive, rod-shaped, obligate aerobic bacteria that belong to the order Actinomycetales and family Mycobacteriaceae. This *Mtb* complex includes (subspecies *M. canetti*), *M. bovis*, *M. microti, M. africanum*, *M. caprae*, *M. bovis* BCG, and *M. pinnipedii* [10]. The cough in a TB patient is caused by the infection of *Mtb* and distributed to air during coughing. The healthy persons who inhaled air droplets of TB infected person and make contact become infected [11].

#### **Tuberculosis-HIV Combination:**

The current opinion disclosed that one-third of the 42 million people living with HIV/AIDS all around the world are co-infected with TB. As per the WHO report, about 90% of the patients containing both TB and HIV died within only some months after clinical indications have arisen. Thus, WHO warned the world of the "even bigger TB-HIV crisis" and explained for extensive accessibility of free anti-TB drugs to individuals living with HIV. The HIV cases are spreading quickly in India with the biggest number of TB cases all around the world [12–15].

#### **3. Chemotherapy of tuberculosis**

#### **First-line anti-TB drugs:**

Treatment of TB is mainly dependent on first-line anti-TB drugs (**Figure 1**), which comprises SM, INH, RMP, EMB, and PZA, these are more effective and less toxic effects as compare to second-line anti-TB drugs [15].

**Drugs for HIV/TB**

*Structures of different antibiotics (second-line drugs).*

**Figure 2.**

**Figure 1.**

*Structures of first-line anti-TB drugs.*

HIV/AIDS [4, 15].

**33**

Clarithromycin (**Figure 5**) is a macrolide antibiotic drug used in HIV infected

erythromycin but is more efficient against certain Gram-negative bacteria, mainly *Legionella pneumophila*. Thioacetazone (**Figure 5**) is valuable in stopping resistance to more influential drugs like INH and RIF. It is not at all used on its own to treat TB. It uses is declining because it can originate severe skin reactions in HIV positive patients. It is also identified to kill MDR-TB. It is no longer suggested for treatment due to its adverse effects like urination-difficulties, dry mouth, glaucoma, and postural hypotension. The circumstances are further complex by the emergence of MDR-TB and XDR-TB by infections with lethal synergy with

TB patients to cure the *M. avium* complex (MAC). It has an analogous of

*Study of Various Chemically and Structurally Diverse Currently Clinically Used…*

*DOI: http://dx.doi.org/10.5772/intechopen.95538*

#### **Second-line anti-TB drugs:**

According to the WHO, there are six drugs of second-line anti-TB drugs. These drugs are categorized as second-line anti-TB drugs due to one of two potential reasons: 1) they are less active than the first-line anti-TB drugs or more toxic sideeffects or 2). These drugs involve different classes namely, aminoglycosides (**Figure 1**): (kanamycin, amikacin), polypeptide analogs (**Figure 2**): (viomycin, capreomycin), FQs (**Figure 3**): (CPX, MXF, OFX, etc), thioamides: (prothioamide, ethionamides), cycloserine and para-aminosalicylic acid (**Figure 4**) [2–4].

*Study of Various Chemically and Structurally Diverse Currently Clinically Used… DOI: http://dx.doi.org/10.5772/intechopen.95538*

#### **Figure 1.**

representation of the world TB threat. It was predictable that nearly 1 billion more people will be infected with TB in the coming 20 years. However, the number of new TB cases is still growing slowly, 95% occur in developing nations every year, and about one million young women per year are offended with this infectious disease in the developing world. The occurrence of TB is associated with a dense population, deprived sanitation, and, poor diet [6]. Directly observed treatment, short-course (DOTS), is the effective way of the control of TB. The three main anti-TB drugs, isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) are used. These drugs are hepatotoxic and may cause drug-related hepatitis. Despite the success of the DOTS therapy, the appearance of MDR-TB strains, persistently isolated from the sputum of pateints, darkens the future [7]. The expansion in TB incidence during current years is primarily due to the incidence of TB in synergy with the HIV pandemic, which increases the risk of growing the new TB cases were attributable to HIV co-infection, and as well as the emergence of MDR-TB strains [8, 9]. Therefore, the objective of this paper is to review the current status of antimycobacterial

*Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex*

Tuberculosis (TB) is caused by the *Mtb* complex. The mycobacterium is nonmotile, Gram-positive, rod-shaped, obligate aerobic bacteria that belong to the order Actinomycetales and family Mycobacteriaceae. This *Mtb* complex includes (subspecies *M. canetti*), *M. bovis*, *M. microti, M. africanum*, *M. caprae*, *M. bovis* BCG, and *M. pinnipedii* [10]. The cough in a TB patient is caused by the infection of *Mtb* and distributed to air during coughing. The healthy persons who inhaled air

The current opinion disclosed that one-third of the 42 million people living with HIV/AIDS all around the world are co-infected with TB. As per the WHO report, about 90% of the patients containing both TB and HIV died within only some months after clinical indications have arisen. Thus, WHO warned the world of the "even bigger TB-HIV crisis" and explained for extensive accessibility of free anti-TB drugs to individuals living with HIV. The HIV cases are spreading quickly in

Treatment of TB is mainly dependent on first-line anti-TB drugs (**Figure 1**), which comprises SM, INH, RMP, EMB, and PZA, these are more effective and less

According to the WHO, there are six drugs of second-line anti-TB drugs. These

drugs are categorized as second-line anti-TB drugs due to one of two potential reasons: 1) they are less active than the first-line anti-TB drugs or more toxic sideeffects or 2). These drugs involve different classes namely, aminoglycosides (**Figure 1**): (kanamycin, amikacin), polypeptide analogs (**Figure 2**): (viomycin, capreomycin), FQs (**Figure 3**): (CPX, MXF, OFX, etc), thioamides: (prothioamide,

ethionamides), cycloserine and para-aminosalicylic acid (**Figure 4**) [2–4].

droplets of TB infected person and make contact become infected [11].

India with the biggest number of TB cases all around the world [12–15].

toxic effects as compare to second-line anti-TB drugs [15].

drugs.

**2. Etiology and routes of transmission**

**Tuberculosis-HIV Combination:**

**3. Chemotherapy of tuberculosis**

**First-line anti-TB drugs:**

**Second-line anti-TB drugs:**

**32**

*Structures of first-line anti-TB drugs.*

#### **Figure 2.**

*Structures of different antibiotics (second-line drugs).*

### **Drugs for HIV/TB**

Clarithromycin (**Figure 5**) is a macrolide antibiotic drug used in HIV infected TB patients to cure the *M. avium* complex (MAC). It has an analogous of erythromycin but is more efficient against certain Gram-negative bacteria, mainly *Legionella pneumophila*. Thioacetazone (**Figure 5**) is valuable in stopping resistance to more influential drugs like INH and RIF. It is not at all used on its own to treat TB. It uses is declining because it can originate severe skin reactions in HIV positive patients. It is also identified to kill MDR-TB. It is no longer suggested for treatment due to its adverse effects like urination-difficulties, dry mouth, glaucoma, and postural hypotension. The circumstances are further complex by the emergence of MDR-TB and XDR-TB by infections with lethal synergy with HIV/AIDS [4, 15].

IhhA needs metabolic activation. It is also utilized in combinations, INH and RIF

*Study of Various Chemically and Structurally Diverse Currently Clinically Used…*

inhibits the mycobacterial transcription by binds to the β-subunit of DNA-

formulation, it can access CNS and it is sensitive to moisture [2–4].

Rifamycins are natural products from *Amicolaptosis mediterranei* belong ansamycin family and are. These are active towards various bacteria but used

Rifapentine is a cyclopentyl analog of RIF. The benefit over rifampin is less repeated dosing. It inhibits bacterial DNA-dependent RNA polymerase and binds to the β subunit. The RIFs blocks the elongation of the RNA transcript and inhibits gene expression. It also acts as a CYP450 inducer. One remarkable side effect is the discoloration of body fluids. The RIFs are not suggested for use in HIV infected patients. Two RIF analogs are existing for indications other

a. **Rifabutin** (Mycobutin): It is used mostly in MAC infections [2–4].

an anti-TB drug in 1966. It obstructs polymerization of cell wall component lipoarabinomannan and arabinogalactan that interrupted biosynthesis of

arabinan and results in the addition of the lipid carrier deca-prenol

darabinofuranosyl-P-decaprenol and produced bacteriostatic effect [25, 26]. EMB (+) isomer is orally active, 16 times more potent than meso isomer, and 200 times more potent than () isomer. The EMB inhibits the polymerization of cell wall

phosphoarabinose. The EMB interferes with the transfer of arabinose to the cell wall acceptors. EMB is effective only towards energetically dividing cells and its action is synergistic with RIF. Arabinosyl transferase enzyme is a target for the action of EMB in both *Mtbs* and *M. avium*. The enzyme is encoded by the embCAB gene organized as an operon and engaged in the arabinogalactan synthesis [27, 28].

Pyrazinamide (PZA) is a pyrazine derivative of nicotinamide and its mechanism is assumed to be analogous to INH. It has to be metabolically activated and PZAresistant strains of *Mtb* contain a mutation in the hydrolase gene. PZA activity against *Mtb* depends on the anaerobic and acidic conditions. PZA is activated to pyrazine acid by the pyrazinamide/nicotinamidase that encoded by gene pncA [29]. Acidic condition favors the production of protonated pyrazinoic acid that collected in the *Mtb* cell membrane which interrupts cell membrane potential and altered membrane transport [30]. The new target of PZA', clpC1 (Rv3596c) that encodes an ATP-dependent ATPase is liable for protein degradation by the complex struc-

b. **Rifaximin** (Xifaxan): Indicated for the treatment of traveler's diarrhea [2–4].

Ethambutol (EMB) is a bacteriostatic, active against growing bacilli, and used as

Rifampin is a semisynthetic analog of rifamycin and the most effective anti-TB agent with MIC values as low as 0.005 μg/mL. It is used as an oral or parenteral

Rifampicin (RIF) was isolated from *Streptomyces mediterranei* from the soil sample and used as an anti-TB since 1972 [21]. It is still utilized as the best choice of anti-TB drugs. RIF diffuses across *Mtb* cell membrane due its lipophilic nature. RIF

and INH, RIF, and PZA. **Rifampicin**

**Rifamycins**

than TB [2–4].

dependent-RNA polymerase [22–24].

*DOI: http://dx.doi.org/10.5772/intechopen.95538*

almost exclusively against TB [2–4].

**Rifampin (Rifadin)**

**Rifapentine (Priftin)**

**Ethambutol (Myambutol):**

**Pyrazinamide (Aldinamide)**

ture with protease clpP1 and clpP2 [31, 32].

**35**

**Figure 3.**

*Structures of different fluoroquinolones (second-line anti-TB drugs).*

**Figure 4.**

*Structures of different second-line anti-TB drugs.*

**Figure 5.** *Structures of drugs for HIV/TB.*

#### **4. Properties and mechanism of currently used common anti-TB drugs**

#### **4.1 Primary agents**

#### **Isoniazid (Nydrazid, Laniazid)**

It is a bacteriostatic drug against resting cells and bactericidal against dividing microorganisms. Isoniazid (INH) is an anti-TB drug since 1952 and acts as a bactericidal and bacteriostatic for rapidly and slowly growing bacilli. It diffuses across the *Mtb* cell membrane [16]. The INH targets KatG and inhA gene. KatG gene encodes catalase/peroxidase enzyme that activates prodrug and peroxynitrite that are involved in pathways of reactive nitrogen and oxygen intermediates [17, 18]. InhA gene encodes NADH dependent enoyl-Acyl Carrier Protein (ACP)-reductase that causes inhibition of mycolic acid synthesis [19, 20]. The INH is a close to ideal antibiotic and very selective (MIC value 0.025–0.05 μg/mL and other bacteria MIC vale >500 μg/mL). The INH has good oral availability and low toxicity. It Inhibits mycolic acid biosynthesis and targets the enoyl-acyl carrier protein reductase enzyme (InhA) engaged in mycolic acid synthesis. The INH inactivation of

*Study of Various Chemically and Structurally Diverse Currently Clinically Used… DOI: http://dx.doi.org/10.5772/intechopen.95538*

IhhA needs metabolic activation. It is also utilized in combinations, INH and RIF and INH, RIF, and PZA.

#### **Rifampicin**

Rifampicin (RIF) was isolated from *Streptomyces mediterranei* from the soil sample and used as an anti-TB since 1972 [21]. It is still utilized as the best choice of anti-TB drugs. RIF diffuses across *Mtb* cell membrane due its lipophilic nature. RIF inhibits the mycobacterial transcription by binds to the β-subunit of DNAdependent-RNA polymerase [22–24].

#### **Rifamycins**

Rifamycins are natural products from *Amicolaptosis mediterranei* belong ansamycin family and are. These are active towards various bacteria but used almost exclusively against TB [2–4].

#### **Rifampin (Rifadin)**

Rifampin is a semisynthetic analog of rifamycin and the most effective anti-TB agent with MIC values as low as 0.005 μg/mL. It is used as an oral or parenteral formulation, it can access CNS and it is sensitive to moisture [2–4].

#### **Rifapentine (Priftin)**

Rifapentine is a cyclopentyl analog of RIF. The benefit over rifampin is less repeated dosing. It inhibits bacterial DNA-dependent RNA polymerase and binds to the β subunit. The RIFs blocks the elongation of the RNA transcript and inhibits gene expression. It also acts as a CYP450 inducer. One remarkable side effect is the discoloration of body fluids. The RIFs are not suggested for use in HIV infected patients. Two RIF analogs are existing for indications other than TB [2–4].

a. **Rifabutin** (Mycobutin): It is used mostly in MAC infections [2–4].

b. **Rifaximin** (Xifaxan): Indicated for the treatment of traveler's diarrhea [2–4].

#### **Ethambutol (Myambutol):**

Ethambutol (EMB) is a bacteriostatic, active against growing bacilli, and used as an anti-TB drug in 1966. It obstructs polymerization of cell wall component lipoarabinomannan and arabinogalactan that interrupted biosynthesis of darabinofuranosyl-P-decaprenol and produced bacteriostatic effect [25, 26]. EMB (+) isomer is orally active, 16 times more potent than meso isomer, and 200 times more potent than () isomer. The EMB inhibits the polymerization of cell wall arabinan and results in the addition of the lipid carrier deca-prenol phosphoarabinose. The EMB interferes with the transfer of arabinose to the cell wall acceptors. EMB is effective only towards energetically dividing cells and its action is synergistic with RIF. Arabinosyl transferase enzyme is a target for the action of EMB in both *Mtbs* and *M. avium*. The enzyme is encoded by the embCAB gene organized as an operon and engaged in the arabinogalactan synthesis [27, 28].

#### **Pyrazinamide (Aldinamide)**

Pyrazinamide (PZA) is a pyrazine derivative of nicotinamide and its mechanism is assumed to be analogous to INH. It has to be metabolically activated and PZAresistant strains of *Mtb* contain a mutation in the hydrolase gene. PZA activity against *Mtb* depends on the anaerobic and acidic conditions. PZA is activated to pyrazine acid by the pyrazinamide/nicotinamidase that encoded by gene pncA [29]. Acidic condition favors the production of protonated pyrazinoic acid that collected in the *Mtb* cell membrane which interrupts cell membrane potential and altered membrane transport [30]. The new target of PZA', clpC1 (Rv3596c) that encodes an ATP-dependent ATPase is liable for protein degradation by the complex structure with protease clpP1 and clpP2 [31, 32].

**4. Properties and mechanism of currently used common anti-TB drugs**

It is a bacteriostatic drug against resting cells and bactericidal against dividing microorganisms. Isoniazid (INH) is an anti-TB drug since 1952 and acts as a bactericidal and bacteriostatic for rapidly and slowly growing bacilli. It diffuses across the *Mtb* cell membrane [16]. The INH targets KatG and inhA gene. KatG gene encodes catalase/peroxidase enzyme that activates prodrug and peroxynitrite that are involved in pathways of reactive nitrogen and oxygen intermediates [17, 18]. InhA gene encodes NADH dependent enoyl-Acyl Carrier Protein (ACP)-reductase that causes inhibition of mycolic acid synthesis [19, 20]. The INH is a close to ideal antibiotic and very selective (MIC value 0.025–0.05 μg/mL and other bacteria MIC vale >500 μg/mL). The INH has good oral availability and low toxicity. It Inhibits mycolic acid biosynthesis and targets the enoyl-acyl carrier protein reductase enzyme (InhA) engaged in mycolic acid synthesis. The INH inactivation of

**4.1 Primary agents**

*Structures of drugs for HIV/TB.*

**Figure 3.**

**Figure 4.**

**Figure 5.**

**34**

**Isoniazid (Nydrazid, Laniazid)**

*Structures of different second-line anti-TB drugs.*

*Structures of different fluoroquinolones (second-line anti-TB drugs).*

*Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex*
