The mechanisms underlying drug resistance in M. tuberculosis are more complex than was initially proposed. Recent evidence has suggested that mechanisms in addition to gene mutations are involved in regulating the level (MIC) of drug resistance. However the molecular basis of such mechanisms in clinical isolates, where the selective pressure is quite different (and largely unknown) than in vitro generated mutants, remains to be determined. Rifampicin (RIF) is the cornerstone to first-line therap y and resistance to RIF is the gateway to MDR-TB and XDR-TB. This study aims to test the hypothesis that the MIC of RIF in RIF resistant clinical isolates of Mycobacterium tuberculosis is defined by mutations in addition to those in the rpoB gene and that these additional mutations control the intracellular concentration of RIF. Complimentary experimental strategies, namely whole genome sequencing, a candidate gene Q-RT PCR approach will be used in order to maximize the identification of genomi c targets and point mutagenesis to confirm the targets that regulate the intracellular concentration of rifampicin in clinical isolates of M. tuberculosis.