Development of a comprehensive platform for targeting redox homeostasis in Mycobacterium tuberculosis.

The prevalence of drug resistance in Mycobacterium tuberculosis (Mtb) calls for the legitimization of new and highly specific drug targets, focusing on unique pathways. The mycothiol ligase (MshC) and mycothione reductase (Mtr) are two components of the mycobacterial redox homeostasis that display the three key components of antibiotic drug targets; high druggability and the potential to show high specificity and essentiality for the organism. Despite being very attractive targets for tuberculosis, there are still considerable key knowledge gaps that need to be addressed; (i) the role of MshC & Mtr during intracellular growth, persistence and growth under stress conditions, (ii) the crystal structure of Mtr and (iii) the regulation of Mtr within Mtb. Furthermore, (iv) there is no profile that allows for the identification and categorization of potential MshC or Mtr inhibitors and (v) specific inhibitors for MshC or Mtr are yet to be discovered. In contrast to previous drug discovery programs to identify MshC or Mtr specific inhibitors, we will approach the targets in a multidisciplinary approach. We will connect three research groups with complimentary expertise in Microbiology, Computer Assisted Drug Design, Structural Biology and Medicinal Chemistry to address the  knowledge gaps outlined above. This can lead to the development of novel treatment strategies for TB and can shorten therapy length.