resistance issue of the first-line and second-line TB drugs can be addressed more
effectively by understanding the novel mechanisms of action of the target concerned and also the pharmacokinetics/pharmacodynamic properties of the drug
variability arising in different patient populations. The application of computational
Table 1 First- and second-line drugs for the treatment of sensitive and drug-resistant TB disease
S. no.
Drugs
Targets involved in drug
binding
Molecular mechanism of drug
action
First line of drugs for drug-sensitive TB cases
1
Isoniazid
Enoyl-acyl-carrier protein
reductase InhA
Inhibition of mycolic acid
synthesis
2
Pyrazinamide
Multiple targets: FAS I,
QAPRTase, RpsA, PanD,
Rv2783 of Mtb
Membrane energetic
disruption, fatty acid and
ribosomal protein synthesis
inhibition
3
Rifampicin
RNA polymerase b subunit
Inhibits transcription
4
Ethambutol
Arabinosyltransferase
Inhibits arabinogalactan
biosynthesis
Second line of drugs for drug-resistant TB cases
1
Streptomycin
Amikacin
16S rRNA subunit of Mtb
ribosome
Inhibits protein synthesis
2
Kanamycin
Capreomycin
30S rRNA subunit of Mtb
ribosome
Inhibits protein synthesis
3
Gatifloxacin
Levofloxacin
Moxifloxacin
DNA gyrase and
topoisomerase
Inhibits DNA synthesis
4
Linezolid
23S rRNA of 50S subunit
Inhibits protein synthesis
5
Clofazimine
Bacterial DNA
Inhibits template function of
DNA
6
Ethionamide
Enoyl-acyl-carrier protein
reductase InhA by activating
catalase peroxidase of Mtb
Inhibits mycolic acid synthesis
7
Cycloserine
Alanine racemase and Dalanine: D-alanine ligase
Inhibits peptidoglycan
synthesis
8
Para-amino
salicylic acid
Dihydrofolate reductase
Inhibits folate biosynthesis
Other drugs for TB chemotherapy (WHO Group D Add on drugs)
1
Delamanid
Pretomanid
Not exactly known
Inhibits mycolic acid synthesis
2
Bedaquiline
ATP synthase subunit c
encoded by atpE gene
Inhibits ATP production
3
Thioacetazone
Mycolic acid cyclopropane
synthases
Inhibits mycolic acid synthesis
4
Meropenem
D,D-transpeptidase and
L,D-transpeptidase
Inhibits peptidoglycan
biosynthesis
Impact of Target-Based Drug Design in Anti-bacterial …
311
effectively by understanding the novel mechanisms of action of the target concerned and also the pharmacokinetics/pharmacodynamic properties of the drug
variability arising in different patient populations. The application of computational
Table 1 First- and second-line drugs for the treatment of sensitive and drug-resistant TB disease
S. no.
Drugs
Targets involved in drug
binding
Molecular mechanism of drug
action
First line of drugs for drug-sensitive TB cases
1
Isoniazid
Enoyl-acyl-carrier protein
reductase InhA
Inhibition of mycolic acid
synthesis
2
Pyrazinamide
Multiple targets: FAS I,
QAPRTase, RpsA, PanD,
Rv2783 of Mtb
Membrane energetic
disruption, fatty acid and
ribosomal protein synthesis
inhibition
3
Rifampicin
RNA polymerase b subunit
Inhibits transcription
4
Ethambutol
Arabinosyltransferase
Inhibits arabinogalactan
biosynthesis
Second line of drugs for drug-resistant TB cases
1
Streptomycin
Amikacin
16S rRNA subunit of Mtb
ribosome
Inhibits protein synthesis
2
Kanamycin
Capreomycin
30S rRNA subunit of Mtb
ribosome
Inhibits protein synthesis
3
Gatifloxacin
Levofloxacin
Moxifloxacin
DNA gyrase and
topoisomerase
Inhibits DNA synthesis
4
Linezolid
23S rRNA of 50S subunit
Inhibits protein synthesis
5
Clofazimine
Bacterial DNA
Inhibits template function of
DNA
6
Ethionamide
Enoyl-acyl-carrier protein
reductase InhA by activating
catalase peroxidase of Mtb
Inhibits mycolic acid synthesis
7
Cycloserine
Alanine racemase and Dalanine: D-alanine ligase
Inhibits peptidoglycan
synthesis
8
Para-amino
salicylic acid
Dihydrofolate reductase
Inhibits folate biosynthesis
Other drugs for TB chemotherapy (WHO Group D Add on drugs)
1
Delamanid
Pretomanid
Not exactly known
Inhibits mycolic acid synthesis
2
Bedaquiline
ATP synthase subunit c
encoded by atpE gene
Inhibits ATP production
3
Thioacetazone
Mycolic acid cyclopropane
synthases
Inhibits mycolic acid synthesis
4
Meropenem
D,D-transpeptidase and
L,D-transpeptidase
Inhibits peptidoglycan
biosynthesis
Impact of Target-Based Drug Design in Anti-bacterial …
311