ATP-dependent MurE ligase in Mycobacterium tuberculosis: Biochemical and structural characterisation

An Integration of Interdisciplinary Translational Research in Anti-TB Drug Discovery: Out of the University Research Laboratories to Combat Mycobacterium tuberculosis

“…All these Mur ligases have been found to be essential in a number of pathogenic bacteria. Sequence alignments at the gene and amino acid level, however, clearly indicate significant dissimilarities between these Mur ligases from M. tuberculosis and from other micro-organisms including E. coli [23]. In order to characterize the key biochemical pathway involved in the initial cytoplasmic stages of mycobacterial PG biosynthesis, to date, the mur C, D, E and F genes have been cloned from M. tuberculosis H 37 Rv and the recombinant Mtb-Mur proteins purified from the soluble fraction were shown to be functional.…”

“…Furthermore, presence of divalent cations was found to be an absolute requirement for their activities. Also higher concentrations of ATP and UDP-sugar substrates were inhibitory for the activities of all ATP dependent Mur ligases suggesting a stringent control of the cytoplasmic steps of peptidoglycan biosynthetic pathway in M. tuberculosis [23][24][25].…”

“…Two crystal structures of Mtb-MurE have been solved with different substrates bound to it, and essential residues have been determined for this enzyme by mutation studies [23,24]. A number of initial hits against the Mtb-MurE enzyme have been reported by us recently [28][29][30] and some of these agents are also antibacterial against whole-cell M. tuberculosis, are now part of medicinal chemistry projects to optimize these hits.…”

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

“…The structure of murE has been resolved to 3A and shows an accessible active pocket site that can be exploited for drug design. 124,125 Enzymatic inhibition of MurE from M. tuberculosis was observed with the extracts from Columbian plants and chemically synthesized quinolone compounds thereby demonstrating that the ligases can serve as drug targets. [126][127][128][129] Additionally, as cell division and cell wall biogenesis are stringently controlled, co-operative processes, it is no surprise to find the mur ligase genes clustered in the division cell-wall (dcw) operon, further indicating that targeting this pathway will have knock-on effects on co-regulated pathways.…”

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

“…Peptidoglycan is a major component of the cell wall of almost all eubacteria. Structurally it consists of linear glycan chains with alternating units of N -acetylglucosamine (GlcNAc) and N -acetylmuramic acid (MurNAc), cross-linked by trans peptide bridges [3]. Since it is unique to bacterial cells, the enzymes that catalyse its biosynthesis offer an attractive target for discovery of new antibiotics against TB.…”