The ability of M. tuberculosis to acquire resistance to first and second line drugs is emerging as aworldwide problem that threatens to undermine TB control efforts in high burden settings. Highlysuccessful multi-drug resistant (MDR) and extensively drug resistant (XDR) strains have beenidentified that are readily transmitted between hosts. These strains may result from geneticalterations that lead to a hyper-mutable state which enables rapid acquisition of diversemechanisms of drug inactivation, from compensatory mutations that restore reproductive fitness, orfrom genetic lesions that lead to loss of uptake of drugs into the bacterium. This project willinvestigate these hypotheses using genetic and metabolomic analyses of susceptible, MDR andXDR isolates from human patients. Using well-characterized M. tuberculosis (MTB) isolatesobtained from existing archives as well as prospectively collected specimens, we will develop andvalidate laboratory tools to experimentally measure the mutability of strains of M. tuberculosis anduse these tools to assess this characteristic in clinical drug sensitive and resistant strains. We willalso compare the neutral evolution rates in MDR and drug-sensitive isolates to test forhyper-mutation in these M. tuberculosis populations. Finally we will assess changes in the M.tuberculosis cell wall structure that may correlate with drug resistance and virulence, using a newliquid chromatography-mass spectrometry system for simultaneously measuring thousands of lipidspecies.
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