Whole Genome Sequencing of Clinical Isolates from Patients with Multidrug Resistant Tuberculosis in India 

This study was terminated August 9, 2019.

Comparative genomic analysis using whole genome sequencing (WGS) offers an opportunity to understand the specific mutations associated with drug resistance and the phenotypic behavior of TB. As treatment programs incorporate more molecular diagnostics such as Xpert MTB/RIF and line probe assays, it also becomes important to make use of country-specific probes to improve sensitivity of these assays. Very few TB isolates have been sequenced from India, which limits our knowledge about the local prevalence and variety of resistance mutations. WGS can identify these genomic patterns and may help explain the clinical manifestations of specific TB isolates.

In addition to WGS, proteomic analysis of patient samples may also demonstrate markers of phenotypic susceptibility not available by analysis of genetic markers alone. Once expressed, post-translational modifications (PTMs) such as the phosphorylation of target proteins affect metabolic activity, such as secretion systems, fatty acid metabolism, and response to changes in environmental conditions.  Metabolomic evaluation of these resistant isolates could facilitate the development of vaccines, diagnostic tests, choice of drug targets, and could lead to the development of newer therapeutics against tuberculosis. We propose an evaluation of MDR TB isolates by WGS, proteomic, and metabolomic analysis from Byramjee Jeejeebhoy Medical College (BJMC) and Sassoon General Hospitals (SGH).

STUDY OBJECTIVES

Objective 1: Characterize the frequency of known genome-derived markers for drug resistant TB among Indian patients using whole genome sequencing.

Objective 2: Perform proteomic, phosphoproteomic, and metabolomic profiling of drug resistant TB isolates from India to characterize the phenotypic manifestations of gene mutations and associated those manifestations with known virulence patterns.