Data Intensive Genome Level Analysis for Identifying Novel, Non-Toxic Drug Targets for Multi Drug Resistant Mycobacterium tuberculosis

Abstract

We report the construction of a novel Systems Biology based virtual drug discovery model for the prediction of non-toxic metabolic targets in Mycobacterium tuberculosis (Mtb). This is based on a data-intensive genome level analysis and the principle of conservation of the evolutionarily important genes. In the 1623 sequenced Mtb strains, 890 metabolic genes identified through a systems approach in Mtb were evaluated for non-synonymous mutations. The 33 genes showed none or one variation in the entire 1623 strains, including 1084 Russian MDR strains. These invariant targets were further evaluated for their experimental and in silico essentiality as well as availability of their crystal structure in Protein Data Bank (PDB). Along with this, targets for the common existing antibiotics and the new Tb drug candidates were also screened for their variation across 1623 strains of Mtb for understanding the drug resistance. We propose that the reduced set of these reported targets could be a more effective starting point for medicinal chemists in generating new chemical leads. This approach has the potential of fueling the dried up Tuberculosis (Tb) drug discovery pipeline.

Fluoroquinolone resistance and mutational profile of gyrA in pulmonary MDR tuberculosis patients

“…The emergence of drug resistance and persistence of infection is a serious threat to the control of TB [7]. A high incidence of resistance severely limits treatment options and requires the use of more toxic and costly treatment regimens [8].…”

Structure based drug discovery for designing leads for the non-toxic metabolic targets in multi drug resistant Mycobacterium tuberculosis

“…All the 15 shortlisted targets from our previous analysis [ 10 ] were evaluated using a myriad of structure based drug design approaches. Molecular docking was performed for targets with their corresponding Natural Substrates (NS)/PDB ligand and a maximum of ten different poses were generated for each, in order to understand the best binding poses in the pocket.…”

“…We have previously reported an integrated model involving Systems Biology approach, incorporating an extensive genome wide evaluation, as well as understanding the sites of mutations in 1623 genome of clinical isolates of Mtb, to identify 33 potential non-toxic metabolic targets [ 9 , 10 ]. Our previous work emphasizes the use of systems biology approach to identify novel non-toxic targets with a motivation to shorten the process of drug discovery by exploiting computational methods focusing on Mtb.…”

Fluoroquinolone resistance and mutational profile of gyrA gene in pulmonary MDR tuberculosis patients

“…The emergence of drug resistance and persistence of infection is serious threat to control TB [7]. This high incidence of resistance severely limits treatment options and requires the use of more toxic and costly treatment regimens [8].…”