Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development

Abstract

SUMMARY Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB.

New Insights in to the Intrinsic and Acquired Drug Resistance Mechanisms in Mycobacteria

“…The naturally occurring broad-spectrum antibiotic fosfomycin is a well-known inhibitor of MurA (Alderwick et al, 2015; Moraes et al, 2015). It specifically inhibits MurA by forming a covalent adduct with a cysteine residue in the active site (Moraes et al, 2015).…”

Chemistry of Peptidoglycan in Mycobacterium tuberculosis Life Cycle: An off‐the‐wall Balance of Synthesis and Degradation

“…Mur enzymes have been both biochemically and structurally characterized in different bacteria, although only MurE has been structurally described in M. tuberculosis . Given the sequence identities of these Mur enzymes to their homologs in M. tuberculosis (Table ), structural data for M. tuberculosis Mur proteins could be obtained by homology modelling . These models show that proteins of the Mur class are all structurally unrelated .…”

Computational Approach for Locating Effective Cyanobacterial Compounds against Mycobacterium Tuberculosis

“…The biosynthesis of peptidoglycan layer is catalysed by enzymes, GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF, at several coordinated cytoplasmic and periplasmicsteps (Table 1). 9,10 In the cytoplasmic step, the synthesis of UDP-MurNAc from UDP-GlcNAc is mediated by MurA ligase (UDP-N-acetylglucosamine 1-carboxyvinyl transferase), which was used as a suitable target for the drug development attempt. [9][10][11][12] Previously for drug development, to address drug resistant strains of the Gram-positive bacterium, Enterococcus faecalis as well as, of M. leprae, Mur ligases were shown as target enzymes in molecular docking attempts.…”

“…9,10 In the cytoplasmic step, the synthesis of UDP-MurNAc from UDP-GlcNAc is mediated by MurA ligase (UDP-N-acetylglucosamine 1-carboxyvinyl transferase), which was used as a suitable target for the drug development attempt. [9][10][11][12] Previously for drug development, to address drug resistant strains of the Gram-positive bacterium, Enterococcus faecalis as well as, of M. leprae, Mur ligases were shown as target enzymes in molecular docking attempts. 13,14 Obviously, an in silico computation would help locating a suitable control agent without the hit-andmiss method, which is often followed in drug targeting attempts; in vivo attempts would follow by apothecary, after being suitably indicated by computational work.…”