b-lactams synthesis and antibacterial activity
Glycopeptides synthesis and antibacterial activity
Phosphomycin synthesis and antibacterial activity

Inhibitors of Bacterial Cell Wall Synthesis

A prime target for antimicrobial chemotherapy is the cell wall, since practically all bacteria (with the exception of mycoplasmas) have it, whereas mammalian cells lack this feature. Several groups of antibiotics, notably b-lactam agents (penicillins, cephalosporins, monobactams, carbapenems) and glycopeptides (vancomycin and teicoplanin) act on this specific target. A few less important antibiotics also act at this level and some compounds used in the treatment of tuberculosis and leprosy act on the specialized mycobacterial cell wall.

In general bacterial cell walls conform to two basic patterns, which can be distinguished by that most familiar of all microbiological techniques, the Gram stain. Gram-positive (staphylococci, streptococci, etc.) and Gram-negative (escherichia, pseudomonas, klebsiella, etc.) bacteria respond differently to cell wall active agents and it is helpful to understand the basis for this difference.

Cell wall construction
In both Gram-positive and Gram-negative bacteria the cell wall is formed from a cross-linked chain of alternating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), known as peptidoglycan or mucopeptide. The process of synthesis is illustrated in outline in Fig. 1. NAM is built from NAG by the addition of lactic acid derived from phosphoenolpyruvate. Three amino acids are then added to form a muramic acid tripeptide. Meanwhile, two D-alanine residues, produced from L-alanine by an enzyme called alanine racemase, are joined together by another enzyme, D-alanine synthetase. The linked unit, D-ala-D-ala, is added to the tripeptide and the muramic acid pentapeptide thus formed is joined to NAG and joined to a lipid carrier in the cell membrane. The whole building block is transported across the cell membrane and added to the end of the existing cell wall. Finally, adjacent units are cross-linked to give the wall its strength.

Fig. 1 Simplified scheme of bacterial cell wall synthesis and action sites of cell wall-active antibiotics

In Gram-positive bacteria the cell wall structure is thick (about 30 nm), tightly cross-linked, and embedded with polysugarphosphates (teichoic acids), some of which have a lipophilic tail buried in the cell membrane (lipoteichoic acids). Gram-negative bacteria, in contrast, have a relatively thin (2-3 nm), loosely cross-linked peptidoglycan layer and do not have teichoic acid, but have other components like lipid A. External to the Gram-negative peptidoglycan is a membrane-like structure, composed mainly of lipopolysaccharide and lipoprotein, which prevents large molecules such as glycopeptides from entering the cell. Small hydrophilic molecules enter Gram-negative bacilli through aqueous channels called porins. Differential activity among some groups of antibiotics, notably the penicillins and cephalosporins, is influenced by their ability to pass through these porin channels which largely depend on the size and ionic charge of substituents carried by the antibacterial agents.

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