heme molecule present in the oxygen sensor called DosS/T present in Mtb and
inhibits the bacilli to establish dormancy during hypoxic conditions. However,
further studies are required to better understand the anti-mycobacterial activity of
Artemisinin [127].
Metformin: It is an oral drug which is approved for the treatment of type 2
diabetes mellitus. The first report on Metformin as adjunct anti-tuberculosis therapy
was reported in 2016 [128]. Instead of targeting the Mtb protein, Metformin is
involved in the host-directed therapy, which involves targeting the harmful
inflammation leading to tissue damage. Metformin is an activator of 5’adenosine
monophosphate-activated protein kinase (AMPK), and this in turn increases the
mitochondrial reactive oxygen species (ROS). The macrophages, which are
exposed to Metformin, showed high in vitro anti-mycobacterial activity because of
the increased level of ROS [128]. Briefly, Metformin is shown to promote
phagocytosis, phagosome–lysosome fusion, and autophagy, which are the host
cellular processes evaded by Mtb to survive inside macrophages. Singhal et al.
further confirmed that diabetes mellitus patients on Metformin treatment had higher
control of TB infection [128, 129].
Clofazimine: Clofazimine is a riminophenazine dye used in the leprosy treatment for decades. The efficacy of treating MDR and XDR-TB is already validated,
and it is listed as a WHO-recommended second-line drug for the treatment of TB.
Clofazimine is shown to decrease the TB treatment duration [130]. However, the
main side effect of the drug is skin discoloration owing to its long half life and
higher lipophilic nature [131, 132].
Fig. 7 Molecular interactions of Meropenem with the active of Ldt Mt2 (PDB ID: 4GSU [47]).
(a) The binding site of Meropenem (sticks) and (b) the molecular interactions with the active site
amino acid residues (lines); the catalytic Cys 354 is represented as orange sticks and the covalent
bond with Meropenem is encircled
Impact of Target-Based Drug Design in Anti-bacterial …
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inhibits the bacilli to establish dormancy during hypoxic conditions. However,
further studies are required to better understand the anti-mycobacterial activity of
Artemisinin [127].
Metformin: It is an oral drug which is approved for the treatment of type 2
diabetes mellitus. The first report on Metformin as adjunct anti-tuberculosis therapy
was reported in 2016 [128]. Instead of targeting the Mtb protein, Metformin is
involved in the host-directed therapy, which involves targeting the harmful
inflammation leading to tissue damage. Metformin is an activator of 5’adenosine
monophosphate-activated protein kinase (AMPK), and this in turn increases the
mitochondrial reactive oxygen species (ROS). The macrophages, which are
exposed to Metformin, showed high in vitro anti-mycobacterial activity because of
the increased level of ROS [128]. Briefly, Metformin is shown to promote
phagocytosis, phagosome–lysosome fusion, and autophagy, which are the host
cellular processes evaded by Mtb to survive inside macrophages. Singhal et al.
further confirmed that diabetes mellitus patients on Metformin treatment had higher
control of TB infection [128, 129].
Clofazimine: Clofazimine is a riminophenazine dye used in the leprosy treatment for decades. The efficacy of treating MDR and XDR-TB is already validated,
and it is listed as a WHO-recommended second-line drug for the treatment of TB.
Clofazimine is shown to decrease the TB treatment duration [130]. However, the
main side effect of the drug is skin discoloration owing to its long half life and
higher lipophilic nature [131, 132].
Fig. 7 Molecular interactions of Meropenem with the active of Ldt Mt2 (PDB ID: 4GSU [47]).
(a) The binding site of Meropenem (sticks) and (b) the molecular interactions with the active site
amino acid residues (lines); the catalytic Cys 354 is represented as orange sticks and the covalent
bond with Meropenem is encircled
Impact of Target-Based Drug Design in Anti-bacterial …
329