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Main Research

 

 

Bioinformatics

 

Genome 3D (Modelling the proteome)

 

Mutational Analysis

 

Protein-Ligand binding/Drug design

 

Statistical structural features of protein

 

DNA Repair

 

Non-Homologous End Joining

 

 

Drug Discovery

 

Mycobacterium tuberculosis

Targeting CoA pathway enzymes

Targeting carbohydrate synthesis pathway enzymes

 

Mycobacterium abscessus

Drug discovery against Mycobacterium abscessus in Cystic Fibrosis
Cystic Fibrosis is a serious genetic disease that affects approximately 70,000 people worldwide. The disease is caused by mutations in the gene coding for a plasma membrane-associated anion channel called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). A defective CFTR protein leads to inability of cells of many organs, including lungs, pancreas, gastrointestinal tract, sinuses, and reproductive tract, to maintain ion and fluid homeostasis; this leads to retention of thick secretions, resulting in serious infection and inflammation.

Although, previously thought to be benign environmental microbes, Non-tuberculous Mycobacteria (NTM) are increasingly observed as a cause of chronic lung infections. Recent years have seen the emergence of highly drug-resistant Non-tuberculous mycobacteria such as Mycobacterium abscessus, which leads to progressive inflammatory lung damage in Cystic Fibrosis patients. The bacterium in turn is found to be highly resistant to antibiotics and most anti-tuberculosis drugs, often resulting in therapeutic failure. As part of the strategic research consortium, funded by the Cystic Fibrosis Trust, our lab focuses on identifying effective drugs to treat Mycobacterium abscessus infection in cystic fibrosis by a structure-guided fragment-based drug discovery approach. Three bacterial targets: PPAT (Phosphopantethiene adenylyl transferase): an enzyme involved in the biosynthesis of bacterial CoenzymeA, TrmD (tRNA-(N1G37) methyl transferase): an essential tRNA modifying enzyme in bacteria and PurC (SAICAR synthase): an enzyme of bacterial de-novo Purine biosynthesis, are being studied as part of this project. We were able to define high resolution structures for these target proteins and an optimized system for fragment library screening and hit validation, was developed to identify starting fragments and analogs that hit these targets. These initial hits are now being chemically elaborated and tested to be developed into significantly potent lead molecules. In the longer term, these molecules will be further evaluated on cellular assays and in-vivo models of Mycobacterium abscessus infection, to be ultimately presented as a clinical proof of principle.

 

Growth Factors