In the hunt for new antibiotics with activity against Gramnegative pathogens, the outer membrane beta-barrel assembly machine (BAM) complex has become an increasingly interesting target. The... Show moreIn the hunt for new antibiotics with activity against Gramnegative pathogens, the outer membrane beta-barrel assembly machine (BAM) complex has become an increasingly interesting target. The recently reported BAM complex inhibitor, MRL-494, was discovered via a screening campaign for molecules that target the outer membrane. Notably, MRL-494 was reported to be an unintended byproduct generated during the synthesis of an unrelated compound, and as such no synthesis of the compound was disclosed. We here present a convenient and reliable route for the synthesis of MRL-494 that scales well. The antibacterial activity measured for synthesized MRL-494 matches that reported in the literature. Furthermore, MRL-494 was found to exhibit potent synergistic activity with rifampicin against Gram-negative bacteria, including E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa. MRL-494 was also found to cause outer membrane disruption and induction of the Rcs stress response pathway. In addition, we undertook a focused structure-activity study specifically aimed at elucidating the roles played by the two guanidine moieties contained within the structure of MRL-494. Show less
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... Show moreThe 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. Show less
Bergqvist, D.; Lindeman, J.H.N.; Lindholt, J.S.; Bjorck, M. 2013
