New old challenges in tuberculosis: potentially effective nanotechnologies in drug delivery.

The role of isocitrate lyase (ICL) in the glyoxylate cycle and its necessity for persistence and virulence of Mycobacterium tuberculosis has been well described. Recent reports have alluded to an additional role for this enzyme in M. tuberculosis metabolism, specifically for growth on propionate. A product of beta-oxidation of odd-chain fatty acids is propionyl-CoA. Clearance of propionyl-CoA and the by-products of its metabolism via the methylcitrate cycle is vital due to their potentially toxic effects. Although the genome of M. tuberculosis encodes orthologues of two of the three enzymes of the methylcitrate cycle, methylcitrate synthase and methylcitrate dehydratase, it does not appear to contain a distinct 2-methylisocitrate lyase (MCL). Detailed structural analysis of the MCL from Escherichia coli suggested that the differences in substrate specificity between MCLs and ICLs could be attributed to three conserved amino acid substitutions in the active site, suggesting an MCL signature. However, here we provide enzymatic evidence that shows that despite the absence of the MCL signature, ICL1 from M. tuberculosis can clearly function as a MCL. Furthermore, the crystal structure of ICL1 with pyruvate and succinate bound demonstrates that the active site can accommodate the additional methyl group without significant changes to the structure.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2958.2006.05297.x

Dual Role of Isocitrate Lyase 1 in the Glyoxylate and Methylcitrate Cycles in Mycobacterium Tuberculosis

New anti-tuberculosis drugs in clinical trials with novel mechanisms of action

http://www.boc.uu.se/boc14www/publications/386.pdf

Design, synthesis and biological evaluation of novel triazole, urea and thiourea derivatives of quinoline against Mycobacterium tuberculosis.

Novel three-component domino reactions of ketones, isatin and amino acids: Synthesis and discovery of antimycobacterial activity of highly functionalised novel dispiropyrrolidines

Over recent years, tuberculosis (TB) and disease caused by human immunodeficiency virus (HIV) have merged in a synergistic pandemic. The number of new cases of TB is stabilizing and declining, except in countries with a high prevalence of HIV infection. In these countries, where HIV is driving an increase in the TB burden, the capacity of the current tools and strategies to reduce the burden has been exceeded. This paper summarizes the current status of TB management and describes recent thinking and strategy adjustments required for the control of TB in settings of high HIV prevalence. We review the information on anti-TB drugs that is available in the public domain and highlight the need for continued and concerted efforts (including financial, human and infrastructural investments) for the development of new strategies and anti-TB agents.

/pdf/treatment-of-tuberculosis-present-status-and-future-39hrpkdfgu.pdf

Isabella Ribeiro

Papers

Treatment of tuberculosis: present status and future prospects