Potential Repurposed Drug Candidates for Tuberculosis Treatment.pptx

Drug repurposing untuk penyakit tuberkulosis

1. Potential Repurposed Drug Candidates for Tuberculosis Treatment This comprehensive review discusses the progress of nearly all repurposed drugs identified to date (around 100) that are in development or clinical testing phases against tuberculosis (TB). It emphasizes the efficacy of repurposed drugs in combination with available frontline anti-TB medications and highlights the scope for future investigations. By Dewi

2. Drug Repurposing Strategies and Approaches 1 Screening Identifying potential repurposed drug candidates from a large pool of drugs using appropriate computational or experimental methodologies like molecular docking, pharmacophore modeling, and high throughput drug screening. 2 Shortlisting Selection of potential lead compounds based on the screening results. 3 Validation Validating the discovered drugs through preclinical and clinical trial investigations to evaluate their efficacy, safety, dosage, and synergistic effects.

3. Repurposed Anti-Infective Drugs Antibacterial Agents Drugs like linezolid, clofazimine, carbapenems, cephalosporins, and others have shown promising results against drug-resistant TB strains. Linezolid and clofazimine are already approved by WHO for MDR-TB treatment. Antifungal Agents Azole antifungals like econazole and clotrimazole, as well as artemisinin, have demonstrated anti-TB activity by inhibiting specific enzymes or pathways in Mycobacterium tuberculosis. Anti-Protozoal Agents Drugs like metronidazole, nitazoxanide, pyronaridine, chloroquine, and tafenoquine have shown potential against TB by targeting various mechanisms like inhibiting efflux pumps, disrupting membrane potential, or interfering with mycolic acid biosynthesis.

4. Non-Anti-Infective Repurposed Drugs 1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Drugs like ibuprofen, celecoxib, and aspirin have demonstrated anti-TB effects and are being investigated as adjunctive therapies to reduce inflammation and tissue damage. 2 Anticancer Drugs Compounds such as imatinib, sorafenib, bortezomib, and elesclomol have shown potential against TB by targeting various pathways or mechanisms involved in mycobacterial pathogenesis. 3 Cardiovascular Drugs Drugs like verapamil (calcium channel blocker) and statins (cholesterol-lowering agents) have exhibited anti-TB properties and are being explored as adjunctive therapies. 4 Anti-Psychotic Drugs Certain antipsychotic medications, such as thioridazine, nemonapride, fluspirilene, and pimozide, have demonstrated inhibitory effects against Mycobacterium tuberculosis and are being investigated for repurposing.

5. Miscellaneous Repurposed Drugs Vitamin D Vitamin D has been found to enhance antimicrobial responses and promote autophagy in TB-infected cells, showing potential as an adjunctive therapy. Auranofin This gold-based anti-rheumatic drug has demonstrated broad-spectrum antibacterial activity by targeting thioredoxin reductase and disrupting thiol-redox homeostasis. Thalidomide An immunomodulatory drug, thalidomide has been investigated for its potential to inhibit TNF-α and serve as a host-directed therapy for TB. Disulfiram Originally an alcohol withdrawal drug, disulfiram has shown anti-TB activity by inhibiting the enzyme MetA and altering the methionine pool and redox status.

6. Repurposed Drugs in Clinical Trials Drug Class Mechanism Clinical Trial Phase Linezolid Oxazolidinone Inhibits protein synthesis Phase 3 Clofazimine Riminophenazine Membrane-directed activity Phase 3 Moxifloxacin Fluoroquinolone Inhibits DNA gyrase Phase 3 Levofloxacin Fluoroquinolone Inhibits DNA gyrase Phase 3 Metronidazole Nitroimidazole Breaks DNA helical structure Phase 2 completed Nitazoxanide Thiazolide Disrupts membrane potential Phase 2 completed

7. Combination Therapies with Repurposed Drugs Synergistic Effects Many repurposed drugs have shown synergistic effects when used in combination with standard anti-TB medications, leading to improved efficacy and reduced treatment duration. Adjunctive Therapies Certain repurposed drugs, like ibuprofen, vitamin D, and statins, are being investigated as adjunctive therapies to enhance the host's immune response or reduce inflammation and tissue damage. Host-Directed Therapies Drugs like imatinib, saquinavir, and isoprinosine are being explored as host-directed therapies (HDTs) to modulate the host's immune response and improve treatment outcomes.

8. Repurposed Drugs Targeting Efflux Pumps Verapamil This calcium channel blocker has been found to inhibit efflux pumps in Mycobacterium tuberculosis, potentiating the activity of drugs like bedaquiline and reducing the minimum inhibitory concentrations of rifampicin and isoniazid. Chlorpromazine An antipsychotic drug, chlorpromazine has been shown to inhibit the activity of the NADH:menaquinone oxidoreductase enzyme, which is involved in the energy metabolism pathway of M. tuberculosis. Pranlukast Originally an anti-asthma drug, pranlukast has been identified as a metabolic inhibitor of the arginine biosynthesis pathway in M. tuberculosis, blocking arginine production and impairing bacterial survival. Cyclosporin A This immunosuppressant drug has been found to disrupt biofilm formation in M. tuberculosis by inhibiting the PpiB protein, reducing the dose required for anti-TB drugs like isoniazid and ethambutol.

9. Repurposed Drugs as Host-Directed Therapies Imatinib This anticancer drug has been proposed as a host-directed therapy (HDT) against TB, as it elicits an anti-pathogen host immune response and enhances bacterial clearance. Saquinavir Originally an HIV protease inhibitor, saquinavir has shown potential as an HDT by enhancing antigen presentation, T-cell priming, and IFN-γ secretion against M. tuberculosis. Isoprinosine This synthetic purine derivative has been found to improve host immune responses against M. tuberculosis by producing pro-inflammatory cytokines and increasing T-cell subset proliferation.

10. Challenges and Limitations of Drug Repurposing Data Accessibility Lack of public access to valuable data about drugs, such as clinical trials, and difficulties in handling and integrating certain types of computational data can hinder the repurposing process. Regulatory Hurdles If the available clinical data is obsolete or does not meet regulatory standards, new clinical studies may be required, adding to the time and cost of repurposing. Resistance and Toxicity Some repurposed drugs may have high minimum inhibitory concentrations, toxicities, or contraindications, limiting their potential for TB treatment. Additionally, the unique physiology of M. tuberculosis can lead to rapid resistance development.

11. Intellectual Property Considerations 1 Patent Protection For repositioned drugs, intellectual property (IP) protection is limited, as some national legislations impede obtaining a patent for the second therapeutic use of drugs. 2 Market Entry Restrictions Certain IP laws may restrict the entry of repositioned drugs into the market, posing challenges for their commercialization and availability. 3 Incentives for Research The limited IP protection and potential market restrictions for repositioned drugs may discourage pharmaceutical companies from investing in research and development efforts for drug repurposing.

12. Conclusion and Future Outlook 1 Current Progress The success of repurposed drugs like linezolid, clofazimine, and moxifloxacin in MDR-TB treatment demonstrates the viability of drug repurposing for TB. The rapid advancement of adjunctive therapies like metformin, vitamin D, and statins also shows promise. 2 Combination Approaches Given the potential of combination therapies with repurposed drugs, it is reasonable to expect a combination of host-directed therapies and anti-TB drugs to become the definitive treatment for drug-resistant TB in the near future. 3 Future Research However, challenges and limitations associated with drug repurposing should not be overlooked. Multidisciplinary research on a larger scale is needed to address key questions and overcome obstacles before repurposed drugs can be widely included in TB treatment regimens.