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Introduction
The use of antibiotics to treat microbial infectious diseases represents one of the most important advances in modern medicine. Remarkably, the current major classes of antimicrobial agents target only four cellular processes: cell wall biosynthesis, protein synthesis, DNA replication and repair and folate coenzyme‐dependent thymidine biosynthesis (Walsh, 2003). Within this small set of targets, it can be argued that cell wall biosynthesis has achieved the most extensive clinical utility as inhibitors to this pathway comprise more than 60% of the total antibacterial market, now estimated to be worth more than 25 billion dollars. Recently, the progress of developing agents against the early phases of peptidoglycan biosynthesis has been the subject of a number of reviews (van Heijenoort, 2001; Katz and Caufield, 2003; Silver, 2006; Kotnik et al., 2007). The aim of this report is to review the biology and drug discovery potential of glutamate racemase (MurI), an enzyme involved in the early phases of peptidoglycan biosynthesis.
The bacterial cell wall is a highly cross‐linked polymeric structure consisting of repeating peptidoglycan units of disaccharides (joined in β1‐4 linkage) which contain a novel pentapeptide substitution (for review see van Heijenoort, 2001). Cross‐linking occurs through transpeptidation of the peptide linkages between adjacent glycan strands resulting a structural mesh that acts as a cellular skeleton that protects the cell from rupture due to the osmotic pressure gradient. Inhibition of cell wall production renders the bacteria susceptible to lysis by osmotic pressure and inhibitors that target this pathway are generally cidal.
Peptidoglycan biosynthesis is classified into three distinct phases based on the cellular location of the synthetic machinery. The majority of the clinical success has been achieved through inhibition of the Phase III segment, which involves the extracellular cross‐linking and final maturation of the cellular envelope. While discovery of improved agents that target this phase remains a dominant area of research and development, the burden of resistance continues to rise and limit the therapeutic utility of both the existing and future compounds within these classes. Further, the emergence of multi‐drug‐resistant bacteria, such as methicillin‐resistant Staphylococcus aureus, MDR‐Pseudomonas aeruginosa and MDR‐Acinetobacter baumannii, has resulted in significantly increased mortality rates with limited or no options for therapeutic intervention (