iConcept Press Logo
Email Password Remember me
iConcept Journal of Emerging Issues in Medical Diagnosis and Treatment
iConcept Journal of Emerging Issues in Medical Diagnosis and Treatment
Eugenia Giannopoulou
iConcept Press

iConcept Journal of Emerging Issues in Medical Diagnosis and Treatment

Docking Studies on Novel Drugs Against Drug Resistant Tuberculosis

by Sulochana Somasundaram, R. S. Anand and C. N. Paramsivan

Volume: 2 (2013); Issue: 12


The resurgence of drug resistant tuberculosis and HIV associated intractable mycobacterial infection are of serious global concern. This is due to their potential to survive dormantly in a non-replicating state in protective intracellular niches of Macrophages, dendritic cells, epithelial cells, endothelial cells, fibrocytes, adipocytes and bone marrow stem cells. To contain this situation, new anti-tuberculosis drugs and reduced regimen treatments are of immediate requirement as envisaged by WHO. Development of novel anti-tuberculosis compounds to combat drug resistant tuberculosis is urgently needed. The discovery of new drugs involves several constraints that discourage many companies from investing in new antituberculosis drugs. The research is expensive, slow and difficult, and it requires specialized facilities for handling Mycobacterium tuberculosis (MTB). Due to this situation, it is a matter of urgency to develop new anti-tuberculous drugs, especially with the aid of bioinformatics-based drug design, in order to tackle intractable tuberculosis. The 8-methoxy fluoroquinolones and a nitroimidasole, PA 824 are highly efficacious in showing potent antituberculosis therapeutic activities in humans and animals, particularly when added to multidrug regimens, suggesting their usefulness as first-line drugs for MTB. Especially, PA 824 has been shown to be active against both replicating and non-replicating bacteria. Mutations in the putative fluoroquinolone binding region of the A subunit of gyrase (gyrA) and A76E mutation in the catalytic site of Deazaflavin-dependent nitroreductase (Ddn) have been found to confer high level resistance to fluoroquinolones and PA824 respectively. In view of these mutations, molecular docking analysis was performed to find out novel antagonists that can target the mutant gyrA receptor. The docking studies yielded cholesterol and guanosine conjugated ligands of gatifloxacin (GFX) and moxifloxacin (MFX) as lead structures. Earlier in vitro and in vivo studies have shown an increased activity of conjugated-MFX than free moxifloxacin against persisting MTB within macrophages. Moreover, conjugated-MFX was shown to efficiently localize within the persisting tissues of C57BL/6 mice infected with MTB. In addition, it is also noted that MFX, shows an enhanced activity in the presence of ROS. Since MTB killing mediated by ROS is the key mechanism of PA824, its conjugation with MFX could provide a better synergistic therapeutic advantage against the persisting/dormant MTB that reside in cellular niches such as Bone marrow Mesenchymal stem cells and provide a scope to overcome Multi drug resistant (MDR), Extensively drug resistant (XDR) and possibly Total drug resistant (TDR) Tuberculosis.

Author Details

Sulochana Somasundaram
Dept of Biotechnology, Sri Venkateswara College of Engineering, India
R. S. Anand
Dept of Biotechnology, Anna University, India
C. N. Paramsivan
Head of TB Programme FIND (India) & South East Asia, Foundation for Innovative New Diagnostics, India

Download Full Paper