The biology of Mur ligases as an antibacterial target

Abstract

SummaryWith antibiotic resistance mechanisms increasing in diversity and spreading among bacterial pathogens, the development of new classes of antibacterial agents against judiciously chosen targets is a highpriority task. The biochemical pathway for peptidoglycan biosynthesis is one of the best sources of antibacterial targets. Within this pathway are the Mur ligases, described in this review as highly suitable targets for the development of new classes of antibacterial agents. The amide ligases MurC, MurD, MurE and MurF function with the same catalytic mechanism and share conserved amino acid regions and structural features that can conceivably be exploited for the design of inhibitors that simultaneously target more than one enzyme. This would provide multi-target antibacterial weapons with minimized likelihood of targetmediated resistance development.

Molecular mechanisms of vancomycin resistance

“…Compared to the Ddl ligases which possess narrow specificity for synthesis of d ‐Ala‐ d ‐Ala, Van ligases demonstrate gain of function capabilities supporting not only the formation of a peptide bond between d ‐Ala with various d ‐amino acids but also the formation of an ester bond between the carboxyl terminus of d ‐Ala and d ‐lactate or α‐hydroxy acids . d ‐Ala‐ d ‐lac is further utilized by MurF, which catalyzes the formation of UDP‐MurNAc‐depsipeptide[ d ‐lac], thereby replacing the native peptidoglycan precursor with the vancomycin‐resistant variant. ATP is utilized as a co‐substrate by the d ‐Ala‐ d ‐Ala and d ‐Ala‐ d ‐lac ligases in a two‐step reaction whereby the γ‐phosphate of ATP is transferred to the carboxyl group of d ‐Ala, followed by the second step of condensation of the amino group of d ‐Ala or the hydroxyl group of d ‐lac with the acyl group of the activated d ‐Ala, liberating free phosphate and the product d ‐Ala‐ d ‐Ala or d ‐Ala‐ d ‐lac …”

“…Modification of Lipid II to terminate in d ‐lac or d ‐Ser lowers affinity toward vancomycin. Adapted from…”

The Canadian Institutes of Health Research response to antimicrobial resistance

“…Following an initial workshop and catalyst funding, in September 2010, a team grant involving a partnership between Canada and the U.K. on antibiotic resistance was launched that built on existing collaborations between the two countries and provided four years of support. The first team funded dealt with bacterial cell wall synthesis and is in the process of testing several potential inhibitors with the aim of identifying leads for novel antibiotics (10)(11)(12). The second team studied bacterial resistance to β-lactam antibiotics which led to multiple outcomes, including the design, synthesis and testing of new candidate inhibitors of metallo-β-lactamases, and the characterization of inhibition of key metallo β-lactamases targets by known compounds (13,14).…”

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.…”