**Streptomycin**

Streptomycin (STR) is the first antibiotic cure for TB and it is isolated from the soil microbe *Streptomyces griseus* in 1943 [1]. It is active against growing bacilli, but not active against intracellular and non-growing bacilli. STR is still considered a firstline anti-TB drug but is used less frequently than the other drugs. It has no action against *M. avium*. Resistance is frequently due to phosphorylation. It targets both rpsl and rrs genes that encode 30S ribosomal protein S12 and 16S rRNA, respectively, and finally inhibit the instigation of the translation in the protein synthesis [33, 34].

Fluoroquinolones (FQs) are the derivative of chloroquine in the 1960s and were used as bactericidal in human and veterinary medicines [42]. The FQs are acted by blocking of mycobacterial DNA replication by binding to α and β subunits of DNA gyrase (gyrA and gyrB), which catalyze the supercoiling of DNA and finally,

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

The aminoglycosides (amikacin, kanamycin) and polypeptides (capreomycin, viomyocin) act by inhibiting protein synthesis. Kanamycin and amikacin alter 16S rRNA and capreomycin and viomycin interfere with small and large subunits of the

Capreomycin belongs to the tuberactinomycin family, a highly basic cyclic pentapeptide with a sixth amino acid side chain. It is the most active compound

The most commonly used second-line aminoglycoside and only given by

Linezolid is an oxazolidinone derivative that interrupts the early stage in protein synthesis by binding to the 23S rRNA of the 50S subunit. The gene rplC and rrl are concerned in the action of Linezolid. The rplC gene that encodes 50S ribosomal L3 protein to involve in the synthesis of the ribosomal peptidyltransferase. Hence, rrl gene has 3138 bp length that encodes 23S ribosomal

Fluoroquinolones (FQs) were established into clinical applications in the 1980s and extensively used for the treatment of various bacterial infections [47]. The FQs have been also originated to have anti-TB activity [48] and are presently used as second-line anti-TB drugs. Cross-resistance has been accounted for within

reduced vulnerability to all FQ derivatives [49–51]. With the extensive use of FQSs for the therapy of common microbial infection, resistance to FQs remains uncommon and occurs mostly in MDR strains. The cross-resistance was observed among the various FQ compounds tested (OFX, LVX, GAT, MXF, and CPX) [52]. The rapid progress of resistance is mostly when FQs are used as the only active drugs in a failing multi-drug therapy [53–55]. These new agents are currently taken in

Gatifloxacin (GAT) has bactericidal activity against *Mtb* [56]. It revealed the highest bactericidal effect during the first 2 days. GAT was used in combination with the first-line anti-TB drug INH or RIF: GAT was able to somewhat enhance the bactericidal activity of INH or RIF only for the first 2 days [57]. One study reported that when evaluated in mice in combination with ethionamide and PZA (high doses: 450 mg/kg, 5 days per week). The GAT was capable to clear the lungs of infected

the FQs class such that reduced vulnerability to one FQ possibly presented

**5. Compounds originating from existing families of drugs**

of this family and blocks protein synthesis and interferes with initiation tRNA selection and chain elongation. It binds to a site on 16S rRNA and the 23S rRNA. Some mycobacterium resistant to capreomycin is also resistant to

inhibits DNA synthesis [43].

**Capreomycin (Capastat)**

70S ribosome [44, 45].

kanamycin [2–4]. **Kanamycin**

**Linezolid**

RNA [46].

**Fluoroquinolones**

concern as anti-TB drugs. **Gatifloxacin**

**37**

animals after 2 months of therapy [58].

**Aminoglycosides and polypeptides**

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

intramuscular (IM) administration [14, 15].

#### **Secondary/Retreatment Agents:**

#### **Aminosalicylic Acid (P.A.S. Parasal):**

Para-aminosalicylic acid (PAS) is an oral drug that fell out of use because of adverse effects and frequent resistance. Related to sulfonamides, it is bacteriostatic and acts as a competitive inhibitor of mycobacterial dihydropteroate synthase. There are two mechanisms to produce the desired effect. First, it inhibited folic acid synthesis by the inhibiton of dihydrofolate synthase and dihydropteroate synthase that produces hydroxyl dihydrofolate antimetabolite responsible for the folic acid synthesis [35]. Secondly, it reduced the uptake of iron, that is essential for cell wall component mycobactin synthesis [15].

#### **Ethionamide (Trecator SC):**

Ethionamide (ETH) is developed as a derivative of INH but less potent than INH. Two genes play a role in the mechanism of actions ETH is ethA and inhA. EthA is regulated by the transcriptional repressor ETH [36]. The mechanism of action is like INH. The oxidative activation comes into sight it is by an enzyme other than KatG projected to form a covalent connection with InhA. The mechanism of action of the ETH is a disruption of mycolic acid synthesis by which monooxygenase enzyme activated ETH that binds to NAD+ and forms an adduct which inhibits enoyl acyl-ACP reductase enzyme [37–39] (**Figure 6**).

### **Cycloserine (Seromycin):**

Cycloserine (CYS) is a natural compound and restricted to being retreatment because of CNS toxicity. CYS is a cyclic derivative of serine hydroxamic acid and terizidone. It is isolated from *Streptomyces orchidaceous* in the 1950s. Its acts by interrupting mycobacterial cell wall synthesis by inhibition of L-alanine racemase encoded by alrA that forms D-alanine from L-alanine and D-phenylalanine synthetase crucial for the production of peptidoglycan and cell wall synthesis by the inclusion of Dalanine into pentapeptide [40, 41]. It inhibits peptidoglycan formation, particularly-blocks the alteration of L-Ala to D-Ala.

**Figure 6.** *Presently used anti-TB drugs and sites of action.*

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

Fluoroquinolones (FQs) are the derivative of chloroquine in the 1960s and were used as bactericidal in human and veterinary medicines [42]. The FQs are acted by blocking of mycobacterial DNA replication by binding to α and β subunits of DNA gyrase (gyrA and gyrB), which catalyze the supercoiling of DNA and finally, inhibits DNA synthesis [43].

#### **Aminoglycosides and polypeptides**

The aminoglycosides (amikacin, kanamycin) and polypeptides (capreomycin, viomyocin) act by inhibiting protein synthesis. Kanamycin and amikacin alter 16S rRNA and capreomycin and viomycin interfere with small and large subunits of the 70S ribosome [44, 45].

#### **Capreomycin (Capastat)**

Capreomycin belongs to the tuberactinomycin family, a highly basic cyclic pentapeptide with a sixth amino acid side chain. It is the most active compound of this family and blocks protein synthesis and interferes with initiation tRNA selection and chain elongation. It binds to a site on 16S rRNA and the 23S rRNA. Some mycobacterium resistant to capreomycin is also resistant to kanamycin [2–4].

#### **Kanamycin**

**Streptomycin**

**Secondary/Retreatment Agents: Aminosalicylic Acid (P.A.S. Parasal):**

component mycobactin synthesis [15]. **Ethionamide (Trecator SC):**

**Cycloserine (Seromycin):**

*Presently used anti-TB drugs and sites of action.*

**Figure 6.**

**36**

Streptomycin (STR) is the first antibiotic cure for TB and it is isolated from the soil microbe *Streptomyces griseus* in 1943 [1]. It is active against growing bacilli, but not active against intracellular and non-growing bacilli. STR is still considered a firstline anti-TB drug but is used less frequently than the other drugs. It has no action against *M. avium*. Resistance is frequently due to phosphorylation. It targets both rpsl and rrs genes that encode 30S ribosomal protein S12 and 16S rRNA, respectively, and finally inhibit the instigation of the translation in the protein synthesis [33, 34].

*Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex*

Para-aminosalicylic acid (PAS) is an oral drug that fell out of use because of adverse effects and frequent resistance. Related to sulfonamides, it is bacteriostatic and acts as a competitive inhibitor of mycobacterial dihydropteroate synthase. There are two mechanisms to produce the desired effect. First, it inhibited folic acid synthesis by the inhibiton of dihydrofolate synthase and dihydropteroate synthase that produces hydroxyl dihydrofolate antimetabolite responsible for the folic acid synthesis [35]. Secondly, it reduced the uptake of iron, that is essential for cell wall

Ethionamide (ETH) is developed as a derivative of INH but less potent than INH. Two genes play a role in the mechanism of actions ETH is ethA and inhA. EthA is regulated by the transcriptional repressor ETH [36]. The mechanism of action is like INH. The oxidative activation comes into sight it is by an enzyme other than KatG projected to form a covalent connection with InhA. The mechanism of

monooxygenase enzyme activated ETH that binds to NAD+ and forms an adduct

Cycloserine (CYS) is a natural compound and restricted to being retreatment because of CNS toxicity. CYS is a cyclic derivative of serine hydroxamic acid and terizidone. It is isolated from *Streptomyces orchidaceous* in the 1950s. Its acts by interrupting mycobacterial cell wall synthesis by inhibition of L-alanine racemase encoded by alrA that forms D-alanine from L-alanine and D-phenylalanine synthetase crucial for the production of peptidoglycan and cell wall synthesis by the inclusion of Dalanine into pentapeptide [40, 41]. It inhibits peptidoglycan forma-

action of the ETH is a disruption of mycolic acid synthesis by which

which inhibits enoyl acyl-ACP reductase enzyme [37–39] (**Figure 6**).

tion, particularly-blocks the alteration of L-Ala to D-Ala.

The most commonly used second-line aminoglycoside and only given by intramuscular (IM) administration [14, 15].

#### **Linezolid**

Linezolid is an oxazolidinone derivative that interrupts the early stage in protein synthesis by binding to the 23S rRNA of the 50S subunit. The gene rplC and rrl are concerned in the action of Linezolid. The rplC gene that encodes 50S ribosomal L3 protein to involve in the synthesis of the ribosomal peptidyltransferase. Hence, rrl gene has 3138 bp length that encodes 23S ribosomal RNA [46].

#### **5. Compounds originating from existing families of drugs**

#### **Fluoroquinolones**

Fluoroquinolones (FQs) were established into clinical applications in the 1980s and extensively used for the treatment of various bacterial infections [47]. The FQs have been also originated to have anti-TB activity [48] and are presently used as second-line anti-TB drugs. Cross-resistance has been accounted for within the FQs class such that reduced vulnerability to one FQ possibly presented reduced vulnerability to all FQ derivatives [49–51]. With the extensive use of FQSs for the therapy of common microbial infection, resistance to FQs remains uncommon and occurs mostly in MDR strains. The cross-resistance was observed among the various FQ compounds tested (OFX, LVX, GAT, MXF, and CPX) [52]. The rapid progress of resistance is mostly when FQs are used as the only active drugs in a failing multi-drug therapy [53–55]. These new agents are currently taken in concern as anti-TB drugs.

#### **Gatifloxacin**

Gatifloxacin (GAT) has bactericidal activity against *Mtb* [56]. It revealed the highest bactericidal effect during the first 2 days. GAT was used in combination with the first-line anti-TB drug INH or RIF: GAT was able to somewhat enhance the bactericidal activity of INH or RIF only for the first 2 days [57]. One study reported that when evaluated in mice in combination with ethionamide and PZA (high doses: 450 mg/kg, 5 days per week). The GAT was capable to clear the lungs of infected animals after 2 months of therapy [58].
