The bacterial cell wall, also known as the peptidoglycan, or murein, layer, plays an essential role in the life of the bacterial cell. This fact, combined with the lack of a similar structure in human cells, has made the cell wall the focus of attention for the development of bactericidal agents that are relatively nontoxic for humans.

β-Lactam (Beta-Lactam) Antimicrobial Agents. β-lactam antibiotics have a four-member, nitrogen-containing, β-lactam ring at the core of their structure (Figure 1). The antibiotics differ in ring structure and attached chemical groups. This drug class comprises the largest group of antibacterial agents, and dozens of derivatives are available for clinical use. Types of β-lactam agents include penicillins, cephalosporins, carbapenems, and monobactams. The popularity of these agents results from their bactericidal action and lack of toxicity to humans; also, their molecular structures can be manipulated to achieve greater activity for wider therapeutic applications.

Fig1. Basic structures and examples of commonly used  β-lactam antibiotics. The core β-lactam ring is highlighted in yellow  in each structure. (Modified from Salyers AA, Whitt DD, editors:  Bacterial pathogenesis: a molecular approach, Washington, DC,  1994, ASM Press.)

The β-lactam ring is the key to the mode of action of these drugs. It is structurally similar to acyl-D-alanyl-D alanine, the normal substrate required for synthesis of the linear glycopeptide in the bacterial cell wall. The β-lactam binds the enzyme, inhibiting transpeptidation and cell wall synthesis. Most bacterial cells cannot survive once they have lost the capacity to produce and maintain their peptidoglycan layer. The enzymes essential for this function are anchored in the cell membrane and are referred to as penicillin-binding proteins (PBPs). Bacterial species may have four to six different types of PBPs. The PBPs involved in cell wall cross-linking (i.e., trans peptidases) are often the most critical for survival. When β-lactams bind to these PBPs, cell wall synthesis is essentially halted. Death results from osmotic instability caused by faulty cell wall synthesis, or binding of the β-lactam to PBP may trigger a series of events that leads to autolysis and death of the cell.

Because nearly all clinically relevant bacteria have cell walls, β-lactam agents act against a broad spectrum of gram-positive and gram-negative bacteria. However, because of differences among bacteria in their PBP content, natural structural characteristics (e.g., the outer membrane present in gram-negative but not gram -positive bacteria), and their common antimicrobial resistance mechanisms, the effectiveness of β-lactams against different types of bacteria can vary widely. Gram-positive bacteria secrete β-lactamase into the environment, whereas beta-lactamases produced by gram-negative bacteria remain in the periplasmic space, providing increased protection from the antimicrobial. In addition, any given β-lactam drug has a specific group or type of bacteria against which it is considered to have the greatest activity. The type of bacteria against which a particular antimicrobial agent does and does not have activity is referred to as that drug’s spectrum of activity. Many factors contribute to an antibiotic’s spectrum of activity, and knowledge of this spectrum is the key to many aspects of antimicrobial use and laboratory testing.

A common mechanism of bacterial resistance to β-lactams is the production of enzymes (i.e., β-lactamases) that bind and hydrolyze these drugs. Just as there is a variety of β-lactam antibiotics, there is a variety of β-lactamases. The β-lactamases are grouped into four major categories; classes A, B, C, and D. Classes A and D are considered serine peptidases; class C comprises cephalosporinases; and class B, which requires zinc, is called a metallo-β-lactamase. β-lactamase genes should be located on plasmids or transposons, within an integron, or within the chromosome of the organism. An integron is a large cassette region that contains antibiotic resistance genes and the enzyme integrase, which is required for movement of the cassette from one genetic element to another. In addition, the antimicrobial may be constitutively produced, continuously produced, or it may be induced by the presence of a β-lactam.

Bacteria normally susceptible to β-lactams have developed several resistance mechanisms against the antimicrobials. These include genetic mutations in the PBP coding sequence, altering the structure and reducing the binding affinity to the drug; genetic recombination, resulting in a PBP structure resistant to binding of the drug; overproduction of normal PBP, resulting in over load of the drug; and acquiring a new genetic coding sequence for PBP from another organism with a lower affinity to the drug. These acquired types of β-lactam resistance are more commonly found in gram-positive bacteria.

To circumvent the development of antimicrobial resistance, β-lactam combinations comprised of a β-lactam with antimicrobial activity (e.g., ampicillin, amoxicillin, piperacillin) and a beta-lactam without activity capable of binding and inhibiting β-lactamases (e.g., sulbactam, clavulanate, tazobactam) have been developed. The binding β-lactam “ties up” the β-lactamases produced by the bacteria and allows the other β-lactam in the combination to exert its antimicrobial effect. Examples of these β-lactam/β-lactamase inhibitor combinations include ampicillin/sulbactam, amoxicillin/clavulanate, and piperacillin/tazobactam. Such combinations are effective only against organisms that produce β-lactamases that are bound by the inhibitor; they have little effect on resistance that is mediated by altered PBPs.

Glycopeptides and Lipopeptides. Glycopeptides are the other major class of antibiotics that inhibit bacterial cell wall synthesis by binding to the end of the peptidoglycan, interfering with transpeptidation. This is a different mechanism from that of the β-lactams, which bind directly to the enzyme. Two such antibiotics, vancomycin and teicoplanin, are large molecules and function differently from β-lactam antibiotics (Figure 2). With glycopeptides, the binding interferes with the ability of the PBP enzymes, such as transpeptidases and transglycosylases, to incorporate the precursors into the growing cell wall. With the cessation of cell wall synthesis, cell growth stops and death often follows. Because glycopeptides have a different mode of action, the resistance to β-lactam agents by gram-positive bacteria does not generally hinder their activity. However, because of their relatively large size, they cannot penetrate the outer membrane of most gram-negative bacteria to reach their cell wall pre cursor targets. Therefore, this agent is usually ineffective against gram-negative bacteria. Teicoplanin is approved for use throughout the world but is not currently available in the United States. When vancomycin is used, its levels should be monitored because the potential for toxicity.

Fig2. Structure of vancomycin, a non–β-lactam antibiotic  that inhibits cell wall synthesis. (Modified from Salyers AA, Whitt DD,  editors: Bacterial pathogenesis: a molecular approach, Washington,  DC, 1994, ASM Press.)

Oritavancin and telavancin, which are lipoglycopeptides, are structurally similar to vancomycin. They are semisynthetic molecules that are glycopeptides that contain hydrophobic chemical groups. However, change in the molecular structure of the lipoglycopeptides provides a mechanism by which they can bind to the bacterial cell membrane, increasing the inhibition of cell wall synthesis. In addition, the lipoglycopeptides increase cell permeability and cause depolarization of the cell membrane potential. These agents also inhibit the trans glycosylation process necessary for cell wall synthesis by complexing with the D-alanyl-D-alanine residues. The lipoglycopeptides’ spectrum of activity is comparable to that of vancomycin but also includes vancomycin intermediate Staphylococcus aureus (VISA).

The lipopeptide daptomycin is the most recently developed antimicrobial capable of exerting its antimicrobial effect by binding and disrupting the cell membrane of gram-positive bacteria. The drug binds to the cytoplasmic membrane and inserts its hydrophobic tail into the membrane, disrupting the permeability and resulting in cell death. Daptomycin has potent activity against gram-positive cocci, including those resistant to other agents such as beta-lactams and glycopeptides (e.g., methicillin-resistant S. aureus [MRSA], vancomycin resistant enterococci [VRE], and vancomycin-resistant S. aureus [VRSA]). Because of the molecule’s size, daptomycin is unable to penetrate the outer membrane of gram negative bacilli and thus is ineffective against these organisms.

Several other cell wall–active antibiotics have been discovered and developed over the years, but toxicity to the human host has prevented their widespread clinical use. One example is bacitracin, which inhibits the recycling of certain metabolites required for maintaining peptidoglycan synthesis. Because of potential toxicity, bacitracin is usually only used as a topical antibacterial agent and internal consumption is generally avoided.

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مواضيع ذات صلة

Inhibitors of Protein Synthesis

Inhibitors of Cell Membrane Function

Sulfonamides and Trimethoprim

Quinolones

Aminoglycosides

Glycopeptides, Lipopeptides, Lipoglycopeptides antibiotics

Macrolides

Chloramphenicol

Tetracyclines

Other β-Lactam Drugs

Cephalosporins

Penicillins