1. Efficacy Study Of Potential Anti-tubercular Molecules:
In-vitro and Ex-vivo
Laxman Nawale, Navnath Rode, Amol Sonawane, Vijay Khedkar, Manisha Arkile, Amar Yeware, Ramesh. A. Joshi, Anjali. P. Likhite, Rohini Joshi, Dhiman Sarkar
National Repository of Small Molecules, National Chemical Laboratory, Pune
Dose Dependent Effect of NR Inhibitors on Wayne's Dormancy Model
Introduction
Tuberculosis: Infectious disease caused by the bacillus Mycobacterium tuberculosis
Second leading infectious killer after HIV/AIDS
In 2013, 8.6 million TB cases were reported out of which 1.3 million died
Emergence of Multi-drug resistant TB (MDR-TB) and extremely drug resistant TB (XDR) for which no drugs are available.
Latency being a cause of recurring TB infection is a major problem in eradication of TB
Dose Dependent Effect of Inhibitors against Active M. tuberculosis H37Ra
Mycobacterium tuberculosis
Courtesy: Alicia Johnson -Human not animals were source of Tuberculosis (TB): Study
Need: Discovery of new antitubercular molecules against active and latent forms
Reasons:
M.tuberculosis bacilli possess a well characterized nitrate metabolic pathway which plays important role in pathogenesis (Khan et. al. 2012)
Increased NarGHJI activity during dormancy induced by oxygen limitation (Khan et. al. 2008)
Nitrate reduction is directly proportional to the number of M.tuberculosis bacilli in culture (Sarkar et. al. (2012)
In vitro and ex-vivo whole cell based assay protocols are already developed for screening diverse compound library (Khan et. al(2012), Singh et al(2005).
We have already screened selected libraries from a stock of ~7500 samples available in NRM
Effect of Inhibitors on M. tuberculosis H37Ra within Macrophage
Efficacy in Intracellular Environment
Nitrate reductase Energy Metabolism
- D.Sarkar, “Int J antimicrob. agents, 2008
Results
Screening of different Anti-tubercular Molecules against M. tuberculosis H37Ra to Identify as Potential Drug
Cytotoxic Effect of Inhibitors against human cancer cell lines
In vitro and ex vivo effect of representative inhibitors against M. tuberculosis H37Ra
Prospects of Compounds
Low cytotoxicity in human cancer cell lines, gram positive and gram negative bacteria
Solubility >500 µM
Easy and low cost synthesis
Identification of novel anti-tubercular molecules from synthetic, natural and nanoparticle class of compounds
Novelty of work
MIC’s are as low as the frontline anti-tubercular drug’s used in DOTS and the Stop TB Strategy recommended by WHO and IPR protected by NCL-CSIR
Conclusions
A set of 55 compounds have been identified as potential anti-tubercular inhibitors
Compounds are efficacious against intracellular M. tuberculosis as well as M. tuberculosis H37Ra residing within macrophage
Cytotoxicity is nil up to 100 µg/ml for human cancer cell lines
The non-toxic properties prove that they can be used as potential anti-tubercular inhibitors
Acknowledgements
Authors are thankful to Director, NCL, Pune, India for providing financial assistance through an In-house project.
Disclosure: Compounds IPR protected by NCL-CSIR
Feb 28, 2014