Cell wall biosynthesis is an important physiological process for bacterial survival. To develop drugs, one must understand the chemistry of the bacterial cell wall. Peptidoglycan is a major component of bacterial cell walls. It is a complex three-dimensional grid that surrounds the entire cell and consists of alternating chains of glycan units that are cross-linked by short peptides. Certain antibiotics interfere with cell wall synthesis, weaken the peptidoglycan scaffold and thereby destroy the integrity of the cell wall structure. Since mammalian cells lack cell walls, inhibition of cell wall biosynthesis is a preferred target for discovering antibacterial agents.
Biosynthesis of the peptidoglycan occurs sequentially within three cellular compartments: cytoplasm, membrane, and periplasm). Peptidoglycan biosynthetic begins in the cytoplasm with the synthesis of a muramyl pentapeptide precursor containing a terminal D-Ala-D-Ala. Some antibiotics interfere with the synthesis of basic peptidoglycan building blocks. For example, D-cycloserine inhibits two enzymes involved in the precursor synthesis, preventing both conversions of L-alanine to D-alanine by racemase, and the construction of D-alanyl-D-alanine by D-Ala-D-Ala ligase. In addition, transpeptidases and transglycosylases link newly formed peptidoglycan structures to the cell wall peptidoglycan matrix. Some antibiotics can inhibit peptidoglycan synthesis by inhibiting these two enzymes. For example, β-lactam antibiotics can inhibit transpeptidases and prevent the assembly of peptidoglycan layers in gram-positive and gram-negative bacteria, while the glycopeptide antibiotic vancomycin can prevent cell wall construction by interfering with glycosyltransferases biosynthesis.
Antibacterial agents that interfere with cell wall synthesis involve some of the most frequently used antibacterial agents and many of them have bactericidal effects, mainly including two major classes -β-Lactam and glycopeptide antibiotics. They control Gram-negative and Gram-positive bacterial infection by inhibition of cell wall synthesis and have been used for many decades.
Although β-lactam antibiotics and glycopeptide antibiotics can treat bacterial infections by inhibiting cell wall biosynthesis, incorrect or excessive use of antibiotics in recent years has increased antibiotic resistance, resulting in less effective treatments than before. As a result, there continues to be a need for developing new treatment strategies for bacterial infections. Creative Biolabs is a leading global contract research organization providing comprehensive, integrated antibacterial drug development services. We can accelerate your drug discovery and development program by providing:
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