UDP-GlcNAc pathway: Potential target for inhibitor discovery against M. tuberculosis

In the past five years, an alarming increase in the number of patients with multidrug resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XDR TB) has been reported, particularly in Eastern Europe, Asia and Southern Africa. Current situation has challenged the control and treatment of tuberculosis (TB) which sparked an emergent need to find new anti-tubercular agents with different chemical scaffolds and mechanisms of action. A very fruitful way to identify novel anti-tubercular agents is the development of compounds that target the enzymes essentially required for the biosynthesis and assembly of the mycobacterial cell wall. Biosynthesis of uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) represents one such pathway. Enzymes involved in UDP-GlcNAc biosynthesis have been predicted to be essential for Mycobacterium tuberculosis growth in vitro. It is a key precursor molecule of M. tuberculosis cell wall, being situated at the branched point of two essential biosynthetic pathways, namely peptidoglycan and a disaccharide linker, D-N-GlcNAc-1-rhamnose. This article provides a comprehensive overview of the present knowledge on the enzymes catalyzing the particular steps of the pathway in M. tuberculosis, with special emphasis put on N-acetylglucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme, which catalyzes the last two steps of this pathway. It also gives an insight into the present knowledge about the inhibitors reported against the enzymes, which could be further used as chemical scaffold for the discovery of more potent anti-TB compounds.