Abstract:MotivationRepurposing of known drugs to newer clinical conditions is a promising avenue for finding novel therapeutic applications for tuberculosis.
MethodsWe performed docking-based virtual screening for 1554 known drugs against two of the potential drug targets, namely trpD and coaA of M. tuberculosis. In the first round of in silico screening we used rigid docking using Glide and AutoDock Vina. We subjected the consistently ranked drugs for induced-fit docking by these tools against the same target proteins… Show more
“…The involvement of Minocycline in inhibiting sonic hedgehog–patched–gli signaling was also reported in the same study . In another study Lymecycline (10 μg/mL) alone and in combination of Isoniazid (0.2 μg/mL) and Rifampin (2 μg/mL) substantially inhibited M.tb growth by 93.47%, 99.25%, and 98.35%, respectively, with trpD as a potential drug target . TrpD encodes an enzyme probable anthranilate phosphoribosyl transferase, required for the tryptophan amino acid biosynthesis pathway .…”
Section: Repurposed Drug Candidates Against Tuberculosissupporting
confidence: 65%
“… 42 In another study Lymecycline (10 μg/mL) alone and in combination of Isoniazid (0.2 μg/mL) and Rifampin (2 μg/mL) substantially inhibited M.tb growth by 93.47%, 99.25%, and 98.35%, respectively, with trpD as a potential drug target. 43 TrpD encodes an enzyme probable anthranilate phosphoribosyl transferase, required for the tryptophan amino acid biosynthesis pathway. 44 Doxycycline was recently identified as a successful adjunctive host directed therapy (HDT) in controlling TB-associated tissue degradation caused by matrix metalloproteinases (MMPs) in Phase II trial research, and the drug is also advised for further larger investigations.…”
Section: Repurposed Drug Candidates Against Tuberculosismentioning
The devastating impact of Tuberculosis (TB) has been a menace to mankind for decades. The World Health Organization (WHO) End TB Strategy aims to reduce TB mortality up to 95% and 90% of overall TB cases worldwide, by 2035. This incessant urge will be achieved with a breakthrough in either a new TB vaccine or novel drugs with higher efficacy. However, the development of novel drugs is a laborious process involving a timeline of almost 20−30 years with huge expenditure; on the other hand, repurposing previously approved drugs is a viable technique for overcoming current bottlenecks in the identification of new anti-TB agents. The present comprehensive review discusses the progress of almost all the repurposed drugs that have been identified to the present day (∼100) and are in the development or clinical testing phase against TB. We have also emphasized the efficacy of repurposed drugs in combination with already available frontline anti-TB medications along with the scope of future investigations. This study would provide the researchers a detailed overview of nearly all identified anti-TB repurposed drugs and may assist them in selecting the lead compounds for further in vivo/clinical research.
“…The involvement of Minocycline in inhibiting sonic hedgehog–patched–gli signaling was also reported in the same study . In another study Lymecycline (10 μg/mL) alone and in combination of Isoniazid (0.2 μg/mL) and Rifampin (2 μg/mL) substantially inhibited M.tb growth by 93.47%, 99.25%, and 98.35%, respectively, with trpD as a potential drug target . TrpD encodes an enzyme probable anthranilate phosphoribosyl transferase, required for the tryptophan amino acid biosynthesis pathway .…”
Section: Repurposed Drug Candidates Against Tuberculosissupporting
confidence: 65%
“… 42 In another study Lymecycline (10 μg/mL) alone and in combination of Isoniazid (0.2 μg/mL) and Rifampin (2 μg/mL) substantially inhibited M.tb growth by 93.47%, 99.25%, and 98.35%, respectively, with trpD as a potential drug target. 43 TrpD encodes an enzyme probable anthranilate phosphoribosyl transferase, required for the tryptophan amino acid biosynthesis pathway. 44 Doxycycline was recently identified as a successful adjunctive host directed therapy (HDT) in controlling TB-associated tissue degradation caused by matrix metalloproteinases (MMPs) in Phase II trial research, and the drug is also advised for further larger investigations.…”
Section: Repurposed Drug Candidates Against Tuberculosismentioning
The devastating impact of Tuberculosis (TB) has been a menace to mankind for decades. The World Health Organization (WHO) End TB Strategy aims to reduce TB mortality up to 95% and 90% of overall TB cases worldwide, by 2035. This incessant urge will be achieved with a breakthrough in either a new TB vaccine or novel drugs with higher efficacy. However, the development of novel drugs is a laborious process involving a timeline of almost 20−30 years with huge expenditure; on the other hand, repurposing previously approved drugs is a viable technique for overcoming current bottlenecks in the identification of new anti-TB agents. The present comprehensive review discusses the progress of almost all the repurposed drugs that have been identified to the present day (∼100) and are in the development or clinical testing phase against TB. We have also emphasized the efficacy of repurposed drugs in combination with already available frontline anti-TB medications along with the scope of future investigations. This study would provide the researchers a detailed overview of nearly all identified anti-TB repurposed drugs and may assist them in selecting the lead compounds for further in vivo/clinical research.
Effective therapeutic regimens for the treatment of tuberculosis (TB) are limited. They are comprised of multiple drugs that inhibit the essential cellular pathways in
Mycobacterium tuberculosis
(
Mtb
). The present study investigates an approach which enables a combination of Amoxicillin-Clavulanic acid (AMC) and a repurposed drug for its synergistic effect towards TB treatment. We identified Diosmin (DIO), by targeting the active site residues of L,D-transpeptidase (Ldt) enzymes involved in
Mtb
cell wall biosynthesis by using a structure-based drug design method. DIO is rapidly converted into aglycone form Diosmetin (DMT) after oral administration. Binding of DIO or DMT towards Ldt enzymes was studied using molecular docking and bioassay techniques. Combination of DIO (or DMT) and AMC exhibited higher mycobactericidal activity against
Mycobacterium marinum
as compared to individual drugs. Scanning electron microscopy study of
M. marinum
treated with AMC-DIO and AMC-DMT showed marked cellular leakage.
M. marinum
infected
Drosophila melanogaster
fly model showed an increased fly survival of ~60% upon treatment with a combination of AMC and DIO (or DMT). Finally, the enhanced
in vitro
antimicrobial activity of AMC-DIO was validated against
Mtb
H37Ra and a MDR clinical isolate. Our results demonstrate the potential for AMC and DIO (or DMT) as a synergistic combination for the treatment of TB.
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