A proteomic portrait of Mycobacterium tuberculosis

The ongoing spread of (multi-)drug resistant Mycobacterium tuberculosis presents a major burden on the management of tuberculosis (TB). Early detection of drug resistance or drug tolerance can be essential to minimize the spread of resistant strains. Furthermore, a better knowledge of interstrain variation, mechanisms of action of anti-TB drugs and mycobacterial drug tolerance will facilitate the development of improved diagnostic assays, new drug targets and novel drug treatment strategies. In this thesis, we made use of mass spectrometry-based proteomics as an unbiased hypothesis generating tool to study protein regulation in M. tuberculosis in relation to the development and transmission of drug resistance. The research presented in this thesis has increased our understanding of the mechanisms that provide rifampicin tolerance, the limitations of drug susceptibility testing, inter- and intra-strain variation in M. tuberculosis, thioridazine’s mechanism of action and potential new diagnostic methods. Although we found that the phenotype of emerging M. tuberculosis lineages can be more equipped to withstand antibiotic treatment, the outcomes of this thesis indicate that if we advance our understanding of the etiology of drug resistance in M. tuberculosis, improved treatment strategies and diagnostic methods will be on the horizon.