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Updated: Jun 14, 2025
System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
Published on: April 5, 2017
Design of RNA Polymerase Inhibitors as Therapeutics for Tuberculous Meningitis
Varalakshmi Vummidi1, Sekhar Talluri1
1Department of Biotechnology, GITAM School of Technology, GITAM, Gandhi Nagar, Rushikonda, 530045, Visakhapatnam, Andhra Pradesh, India.
Background:
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. The current treatment protocols for pulmonary tuberculosis are quite effective, even though the treatment requires 3-6 months. The current treatment protocols for extrapulmonary tuberculosis are based on the same drugs that are used for pulmonary tuberculosis. However, the success rates are much lower for certain types of extrapulmonary tuberculosis, such as tuberculous meningitis. Tuberculous meningitis is one of the very few diseases attributable to bacteria that have a very high short-term mortality rate among diagnosed patients, even after treatment with antibiotics that are effective for pulmonary tuberculosis. For example, rifampicin is highly effective for the treatment of pulmonary tuberculosis, but its effectiveness for the treatment of tuberculous meningitis is much lower. The reason for the lower effectiveness of rifampicin against tuberculous meningitis is that it has low Blood-Brain Barrier (BBB) permeability, which results in lower concentrations of the drug at the required sites in the central nervous system.
Methods:
In this work, ligands having improved BBB permeability and pharmacokinetic and pharmacodynamic properties, either similar to or better than that of rifampicin, have been designed. The BBB permeability of the designed molecules was assessed by using pkCSM, a machine- learning model. Pharmacokinetic properties, drug-likeness, and synthesizability were assessed by using SWISS-MODEL. The binding affinity of the designed drugs was assessed by using AutoDock Vina. A customized scoring function, StWN score, was used for a quantitative weighted assessment of all the properties of interest to rank the designed molecules.
Results:
In this study, drug-like ligands have been designed that have been predicted to have high BBB permeability as well as high affinity for RNA polymerase β of Mycobacterium tuberculosis.
Conclusion:
The best ligands generated by the tools employed were selected as potential drugs to address the current need for better options for the treatment of tuberculous meningitis.
Insights
Researchers designed new drug candidates to treat tuberculous meningitis, a severe infection caused by Mycobacterium tuberculosis. These novel ligands show improved Blood-Brain Barrier permeability and high affinity for the target pathogen, offering potential new treatments.
Area of Science:
- Drug discovery and development
- Infectious diseases
- Neuroscience
Background:
- Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis.
- Current TB treatments are effective for pulmonary TB but less so for extrapulmonary forms, particularly tuberculous meningitis.
- Tuberculous meningitis has a high mortality rate due to low drug penetration into the central nervous system, such as rifampicin's limited Blood-Brain Barrier (BBB) permeability.
Purpose of the Study:
- To design novel ligands with enhanced Blood-Brain Barrier (BBB) permeability and improved pharmacokinetic/pharmacodynamic properties.
- To identify potential drug candidates for treating tuberculous meningitis.
Main Methods:
- Designed ligands with improved BBB permeability using machine learning (pkCSM).
- Assessed pharmacokinetic properties, drug-likeness, and synthesizability (SWISS-MODEL).
- Evaluated binding affinity to Mycobacterium tuberculosis RNA polymerase β (AutoDock Vina) and ranked molecules using a custom scoring function (StWN score).
Main Results:
- Successfully designed drug-like ligands predicted to have high BBB permeability.
- These ligands demonstrated high predicted affinity for the RNA polymerase β of Mycobacterium tuberculosis.
- The designed molecules show potential for improved efficacy in treating tuberculous meningitis.
Conclusions:
- The study identified promising drug candidates for tuberculous meningitis treatment.
- These novel ligands possess favorable predicted properties for targeting central nervous system infections.
- The findings address the urgent need for more effective therapeutic options for tuberculous meningitis.
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