Executive Summary : | Despite significant advancements in tuberculosis control, this disease remains a major global health issue. As proteins are the functional entities of the cell, understanding the profile of a resistant strain could help in the improvement of treatment strategy. Compared the proteome of AK and KM resistant and susceptible M.tuberculosis isolates using 2-dimensional gel electrophoresis and mass spectrometry coupled with bioinformatic tools. Among the twelve proteins which were found overexpressed, nine were with defined roles and three with unknown functions. Bioinformatic analysis revealed the presence of conserved motifs and domains in hypothetical proteins. Molecular docking and GPS-PUP analysis showed proper interaction of both drugs with hypothetical proteins and presence of pupylation sites respectively. It is suggested that these molecules might be overexpressed to inhibit the effect of drugs and pupylation might be involved in turnover of modulated proteins by proteasome machinery to overcome the drug stress. Significant changes were observed in the MIC of cloned proteins suggesting their probable roles in conferring resistance. Besides that, another major finding of the study was the overexpression of bacterioferritin, ferritin and Rv0685 suggesting the probable role of iron metabolism in imparting resistance to second line drugs. Drug might be directly targeting the genes/proteins of iron metabolism which could make the host iron unavailable to bacilli. These findings need further exploitation for the development of newer therapeutic agents or molecular markers which can directly be targeted to a gene/protein responsible for resistance so that an extreme condition like XDR-TB can be prevented, which could ultimately lead to broaden the narrow gauge of new or existing therapeutics. |