Peptidoglycan is a promising target in bacterial cell wall for broad-spectrum antibacterial drug discovery, as the disaccharide-pentapeptide peptidoglycan structure is common to both Gram-negative and Gram-positive bacteria. A series of antibiotics (such as penicillin/lactam and vancomycin/glycopeptide classes of antibiotics) targets on peptidoglycan have been developed by now. Creative Biolabs has developed a top drug discovery platform to identify drug targets especially related with peptidoglycan synthesis.
Figure 1. Peptidoglycan synthesis and cleavage (Typas et al. 2012)
Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that form a mesh-like layer outside the plasma membrane of most bacteria. The peptidoglycan structural unit has two major components: a disaccharide composed of N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (GlcNac), and a pentapeptide covalently attached to MurNAc. After the peptidoglycan unit is synthesized in the cytoplasm, it is translocated across the cell membrane to form linear strands and cross-linked with the peptides. Creative Biolabs has the ability to identify all the targets related to peptidoglycan synthesis for our clients.
Antibacterial Agents Related to Peptidoglycan Polymerization
Peptidoglycan polymerization process includes two main parts: transpeptidation reaction and transglycosylation reaction. There are three stages of peptidoglycan processing: before the transglycosylation and transpeptidation reactions (peptidoglycan lipid intermediates); after transglycosylation but before transpeptidation (immature peptidoglycan); and after transglycosylation and transpeptidation (mature peptidoglycan). Some antibiotics inhibit peptidoglycan transpeptidation stage, for example, β-lactam drugs (penicillins, carbapenems, monobactams, and cephalosporins), by forming an acyl complex with the transpeptidase. Creative Biolabs has developed various natural and chemical compounds libraries for our customers targeting on peptidoglycan polymerization especially transpeptidase and transglycosylase.
Antibacterial Agents Related to Synthesis of the Peptidoglycan Unit
Peptidoglycan is synthesized in the cytoplasm before polymerized. The enzymes involve in the synthesis of peptidoglycan have been identified (Table 1). The first step is the production of UDP-GlcNAc from glucosamine-1-phosphate catalyzed by GlmU. The next two synthetic steps convert UDP-GlcNAc into UDP-MurNAc. First, UDP-GlcNAc-enolpyruvate is synthesized helped by the enzyme MurA and then the UDP-GlcNAc- enolpyruvate is converted to UDP-MurNAc. The final four reactions in the pathway involve the sequential addition of amino acids to UDP-MurNAc to form a covalently bound pentapeptide. Inhibitors of enzymes in this process are well suited for developing to antibacterial drugs. Until now, some specific inhibitors of these enzymes have been identified such as bacteriophage proteins and some natural products (including fosfomycin, liposidomycins, and mureidomycins).
Table 1. Peptidoglycan biosynthetic enzymes. (Green 2002)
Antibacterial Agents Related to Peptidoglycan Synthesis
Some target-based antibacterial drugs also include enzymes that involved in peptidoglycan synthesis or polymerization. Creative Biolabs provides target identification service for identifying targets related to peptidoglycan synthesis.
Creative Biolabs' professional group has the ability to identify novel antibacterial drug targets related with peptidoglycan synthesis. For more detailed information, please feel free to contact us or directly sent us an inquiry.
References
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