dormancy of mycobacteria within the host tissues in response to hypoxia, nitric oxide,
carbon monoxide, and ascorbic acid [49–52]. These regulators represent compelling
targets for anti-bacterial drug design towards Mtb. Kaur et al. identified two DevR
mimetic peptides which specifically inhibit the DevR-dependent transcriptional
activity, thereby blocking the survival of Mtb under hypoxic conditions [53]. Gupta
et al. developed a homology model of DevR and used it for structure-based screening
of 2.5 million ZINC compounds. They identified a potential compound and validated
its sterilizing activity against tubercle bacilli by in vitro techniques [54]. Other Mtb
target involved in the regulatory process is PknB. It is a transmembrane serine/
threonine-protein kinase B and plays a crucial role in a number of signal transduction
through phosphorylation of protein and also regulates cell division and differentiation
[55]. Lougheed et al. performed an HTS of *54,000 compounds against PknB target
and identified number of inhibitors with anti-mycobacterial activities in the micromolar range [56]. PknG is another serine/threonine-protein kinase critical in signal
transduction pathway of Mtb, and a few PknG target-based inhibitors are reported. By
adopting a sequential pharmacophore-based virtual screening method and threefold
docking using different search algorithms followed by molecular dynamic simulations, Singh et al. identified few inhibitors against PknG target. The in vitro validation
resulted in three of these compounds with significant inhibitory activity against Mtb
PknG. Further, the Mtb survival studies within the infected THP-1 macrophage cells
demonstrated that NRB04248 compound inhibited the growth of Mtb bovis BCG [57].
The pathogenicity of Mtb is based on the bacilli’s ability to inhibit phagosome
acidification and maturation processes after endocytosized by macrophages.
Tyrosine phosphatase is enzyme which dephosphorylates the host proteins in
human and which is involved in the signaling pathways leading to the prevention of
the initiation of host defense mechanisms, including phagosome acidification. Two
types of tyrosine phosphatase enzymes are present in Mtb, namely tyrosine
phosphatase A (PtpA) and tyrosine phosphatase B (PtpB) [58–60]. Inhibition of
these enzymes leads to the decrease in the proliferation of Mtb in host macrophages
and thus represents a key druggable target for TB therapy.
2.3 Druggable Targets Involved in Mtb Protein Synthesis
In bacterial protein biosynthesis, peptide deformylase (PDF), a metalloprotease
enzyme, plays a pivotal role in the maturation of nascent polypeptides. Hence, PDF
represents a potential druggable target for the TB therapy [61]. In human, PDF
homologue has been identified; however, there is a notable difference among the
Mtb and human PDF proteins. The main difference between them lies in the fingerprint active site motif pattern, in which leucine residue is mutated into glutamic
acid in human PDF [62]. The sequence alignment of both Mtb and human PDF
showed very less identity in the active site region, suggesting the specific residues
involved in both the species for its function [62]. Hence, these major differences
between them enable the design and discovery of novel inhibitors with selective
318
A. C. Pushkaran et al.
carbon monoxide, and ascorbic acid [49–52]. These regulators represent compelling
targets for anti-bacterial drug design towards Mtb. Kaur et al. identified two DevR
mimetic peptides which specifically inhibit the DevR-dependent transcriptional
activity, thereby blocking the survival of Mtb under hypoxic conditions [53]. Gupta
et al. developed a homology model of DevR and used it for structure-based screening
of 2.5 million ZINC compounds. They identified a potential compound and validated
its sterilizing activity against tubercle bacilli by in vitro techniques [54]. Other Mtb
target involved in the regulatory process is PknB. It is a transmembrane serine/
threonine-protein kinase B and plays a crucial role in a number of signal transduction
through phosphorylation of protein and also regulates cell division and differentiation
[55]. Lougheed et al. performed an HTS of *54,000 compounds against PknB target
and identified number of inhibitors with anti-mycobacterial activities in the micromolar range [56]. PknG is another serine/threonine-protein kinase critical in signal
transduction pathway of Mtb, and a few PknG target-based inhibitors are reported. By
adopting a sequential pharmacophore-based virtual screening method and threefold
docking using different search algorithms followed by molecular dynamic simulations, Singh et al. identified few inhibitors against PknG target. The in vitro validation
resulted in three of these compounds with significant inhibitory activity against Mtb
PknG. Further, the Mtb survival studies within the infected THP-1 macrophage cells
demonstrated that NRB04248 compound inhibited the growth of Mtb bovis BCG [57].
The pathogenicity of Mtb is based on the bacilli’s ability to inhibit phagosome
acidification and maturation processes after endocytosized by macrophages.
Tyrosine phosphatase is enzyme which dephosphorylates the host proteins in
human and which is involved in the signaling pathways leading to the prevention of
the initiation of host defense mechanisms, including phagosome acidification. Two
types of tyrosine phosphatase enzymes are present in Mtb, namely tyrosine
phosphatase A (PtpA) and tyrosine phosphatase B (PtpB) [58–60]. Inhibition of
these enzymes leads to the decrease in the proliferation of Mtb in host macrophages
and thus represents a key druggable target for TB therapy.
2.3 Druggable Targets Involved in Mtb Protein Synthesis
In bacterial protein biosynthesis, peptide deformylase (PDF), a metalloprotease
enzyme, plays a pivotal role in the maturation of nascent polypeptides. Hence, PDF
represents a potential druggable target for the TB therapy [61]. In human, PDF
homologue has been identified; however, there is a notable difference among the
Mtb and human PDF proteins. The main difference between them lies in the fingerprint active site motif pattern, in which leucine residue is mutated into glutamic
acid in human PDF [62]. The sequence alignment of both Mtb and human PDF
showed very less identity in the active site region, suggesting the specific residues
involved in both the species for its function [62]. Hence, these major differences
between them enable the design and discovery of novel inhibitors with selective
318
A. C. Pushkaran et al.