These novel structures strongly suggest the presence of yet to be identified key enzymes involved in bacterial lipoprotein biosynthesis [22]. Most pathogenic mycobacteria belong to the group of slow-growing mycobacteria, including Mycobacterium leprae, the causative agent of leprosy and the members
of the Mycobacterium tuberculosis complex (e.g. M. tuberculosis, Mycobacterium africanum, Mycobacterium cannetti, Mycobacterium bovis). Mycobacterium tuberculosis is the causative agent of human tuberculosis, a major cause of death around the world (http://www.who.int/tb/publications/factsheets/en/index.html). HIF-1 pathway Elimination of tuberculosis requires an improved understanding of the host, the pathogen and their interaction for the development of better, more effective drugs and vaccines. Lipoprotein biogenesis is a major virulence factor of M. tuberculosis[23, 24]. Moreover, lipoproteins evidently meet pathogen-associated molecular
patterns (PAMPs) criteria and are well detected by innate immune recognition mechanisms [25]. M. tuberculosis lipoproteins are major antigens and trigger the activation of cellular and humoral immune responses to mycobacteria. Lipoproteins are potent agonists of toll-like receptor 2 (TLR2) which upon long term stimulation has been associated with the down regulation or deviation of the immune response. TLR2 agonist activity has been demonstrated LY2606368 price for several M. tuberculosis lipoproteins including LpqH, LprA, LprG and PstSI [26, 27]. Recently, it was reported that mycobacteria generate and release membrane vesicles (MVs) [28]. Strikingly, MVs from pathogenic mycobacteria as compared to non-pathogenic mycobacteria are enriched in lipoproteins, some of them well known TLR2 agonists. MVs produced a severe TLR2 dependent inflammatory response in vitro and in vivo [28]. Investigations regarding the vaccine potential of MVs from pathogenic mycobacteria elicited a mixed
cellular and humoral immune response. This suggests a vaccine potential of MVs and their lipoproteins against M. tuberculosis. Even though research on lipoproteins in fast-growing Cyclin-dependent kinase 3 mycobacteria contributed to the knowledge of lipoprotein biosynthesis and modification, there is scarcely known anything about lipoprotein modifications and their chemical structures in slow-growing mycobacteria. Mycobacterium bovis bacille Calmette Guerin (BCG) is derived from virulent M. bovis, the causative agent of bovine tuberculosis. The genome of M. bovis BCG is highly similar to the M. tuberculosis genome (>99.5% sequence identity) [29]. M. bovis BCG was first used in 1921 as a live vaccine against tuberculosis. Since then four billion doses have been applied to humans. Still today it is the only licensed tuberculosis vaccine, despite its incomplete protective efficacy, particular against adult lung tuberculosis [30]. Concerning the presence of open reading frames (ORFs) encoding lipoprotein modifying enzymes, both genomes of M. tuberculosis and M.