Peptidoglycan biosynthesis machinery: A rich source of drug targets

Abstract

The range of antibiotic therapy for the control of bacterial infections is becoming increasingly limited because of the rapid rise in multidrug resistance in clinical bacterial isolates. A few diseases, such as tuberculosis, which were once thought to be under control, have re-emerged as serious health threats. These problems have resulted in intensified research to look for new inhibitors for bacterial pathogens. Of late, the peptidoglycan (PG) layer, the most important component of the bacterial cell wall has been the subject of drug targeting because, first, it is essential for the survivability of eubacteria and secondly, it is absent in humans. The last decade has seen tremendous inputs in deciphering the 3-D structures of the PG biosynthetic enzymes. Many inhibitors against these enzymes have been developed using virtual and high throughput screening techniques. This review discusses the mechanistic and structural properties of the PG biosynthetic enzymes and inhibitors developed in the last decade.

Crystal Structure of Bacillus anthracis Phosphoglucosamine Mutase, an Enzyme in the Peptidoglycan Biosynthetic Pathway

“…Bacterial enzymes that participate in the biosynthesis of UDP-GlcNAc are potential targets for antibacterial compounds, as the biosynthetic pathway of UDPGlcNAc differs between prokaryotes and eukaryotes. To date, crystal structures have been reported for each of the bacterial proteins involved in the cytoplasmic steps of UDP-GlcNAc synthesis, with the exception of PNGM (1,7).…”

Tapping into Salmonella typhimurium LT2 genome in a quest to explore its therapeutic arsenal: A metabolic network modeling approach

“…Recently peptidoglycan biosynthesis pathway has been extensively subjected to drug targeting. As the enzymes involved in peptidoglycan biosynthesis are indispensable to bacterial survival and do not have any orthologs in humans [42], which has directed researchers to an intensified research for discovering new drug targets against bacterial pathogens. Peptidoglycan biosynthesis is a multistage process.…”

“…Stage I occurring in cytoplasm involves the formation of monomeric building block, N-acetylglucosamineNacetylmuramyl pentapeptide through action of ten cytoplasmic enzymes. glmM (Phosphoglucosamine mutase) and glmU (Bifunctional protein GlmU) are important stage I enzymes which synthesize UDP-N-acetylglucosamine (UNAG) [42]. UDP-N-acetylmuramic acid (UNAM) synthesis from UNAG involves murA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase) and murB (UDP-N-acetylenolpyruvoylglucosamine reductase) catalyze important reactions in the peptidoglycan precursor synthesis.…”

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

“…The pivotal role of PGN in the bacterial pathogenesis is clearly highlighted by the fact, that the most frequently used antibiotics are targeting the PGN biosynthesis pathway [13]. MDP is a cleavage product and the smallest bioactive motif of PGN that specifically binds to NOD2 and it leads to an activation of NOD2-mediated signal pathways and other pathways [14].…”