The mycobacterial cell wall catabolism: toward the development of new inhibitors – MyCat

The core of the Mycobacterium tuberculosis cell wall consists of a mycolyl-arabinogalactan-peptidoglycan (mAGP) complex which has been the focus of intense research at both structural and biosynthetic levels during the last few decades. Due to its essentiality, the mAGP is also regarded as an attractive drug target. However, despite the impressive progress made over the past 20 years in understanding mAGP biogenesis, the mechanisms by which the tubercle bacilli adapts its cell wall structure/composition in response to various environmental conditions, especially during infection, remain poorly understood. Indeed, the catabolic pathways of the major cell wall-associated components remain extremely obscure. It is expected that deciphering the molecular basis of cell wall degradation may shed new light on the physiology of M. tuberculosis and the ability of the bacilli to regulate and adapt its cell envelope architecture in the infected host. In addition, because of their uniqueness, enzymes involved in the catabolic process and disassembly of mAGP may offer great promise for future therapeutic intervention against tuberculosis.

In this context, our previous work emphasized the capacity of mycobacteria to release mAGP bioactive degradation products that are can modulate the host immune system. In addition, we have recently identified endogenous D-arabinosidase and D-galactosidase activities in mycobacteria that can degrade arabinogalactan. These results further confirm the view that M. tuberculosis has the intrinsic capacity to degrade its own mAGP.

Based on solid preliminary results, the present proposal aims to i) identify and characterize the D-arabinosidases and D-galactosidases, to establish the structures of these enzymes and to determine their biological function(s) with respect to mAGP degradation; ii) decipher the immunomodulatory properties of the glycosidase reaction products in vitro and in vivo in mycobacteria-infected hosts; iii) synthesize specific inhibitors of the glycosidase activities that may interfere or compromise mycobacterial growth and used as scaffolds for future and of innovative therapeutic developments against tuberculosis.