Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 2)

Inhibition of Cell-Wall SynthesisOne major difference between bacterial and mammalian cells is the presence in bacteria of a rigid wall external to the cell membrane. The wall protects bacterial cells from osmotic rupture, which would result from the cells usual marked hyperosmolarity (by up to 20 atm) relative to the host environment. The structure conferring cell-wall rigidity and resistance to osmotic lysis in both gram-positive and gram-negative bacteria is peptidoglycan, a large, covalently linked sacculus that surrounds the bacterium. In gram-positive bacteria, peptidoglycan is the only layered structure external to the cell membrane and is thick (20–80 nm); in...
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Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 2) Chapter 127. Treatment and Prophylaxis of Bacterial Infections (Part 2) Inhibition of Cell-Wall Synthesis One major difference between bacterial and mammalian cells is thepresence in bacteria of a rigid wall external to the cell membrane. The wallprotects bacterial cells from osmotic rupture, which would result from the cellsusual marked hyperosmolarity (by up to 20 atm) relative to the host environment.The structure conferring cell-wall rigidity and resistance to osmotic lysis in bothgram-positive and gram-negative bacteria is peptidoglycan, a large, covalentlylinked sacculus that surrounds the bacterium. In gram-positive bacteria,peptidoglycan is the only layered structure external to the cell membrane and isthick (20–80 nm); in gram-negative bacteria, there is an outer membrane externalto a very thin (1-nm) peptidoglycan layer. Chemotherapeutic agents directed at any stage of the synthesis, export,assembly, or cross-linking of peptidoglycan lead to inhibition of bacterial cellgrowth and, in most cases, to cell death. Peptidoglycan is composed of (1) abackbone of two alternating sugars, N-acetylglucosamine and N-acetylmuramicacid; (2) a chain of four amino acids that extends down from the backbone (stempeptides); and (3) a peptide bridge that cross-links the peptide chains.Peptidoglycan is formed by the addition of subunits (a sugar with its five attachedamino acids) that are assembled in the cytoplasm and transported through thecytoplasmic membrane to the cell surface. Subsequent cross-linking is driven bycleavage of the terminal stem-peptide amino acid. Virtually all the antibiotics that inhibit bacterial cell-wall synthesis arebactericidal. That is, they eventually result in the cells death due to osmotic lysis.However, much of the loss of cell-wall integrity following treatment with cellwall–active agents is due to the bacterias own cell-wall remodeling enzymes(autolysins) that cleave peptidoglycan bonds in the normal course of cell growth.In the presence of antibacterial agents that inhibit cell-wall growth, autolysisproceeds without normal cell-wall repair; weakness and eventual cellular lysisoccur. Antibacterial agents act to inhibit cell-wall synthesis in several ways, asdescribed below. Bacitracin Bacitracin, a cyclic peptide antibiotic, inhibits the conversion to its activeform of the lipid carrier that moves the water-soluble cytoplasmic peptidoglycansubunits through the cell membrane to the cell exterior. Glycopeptides Glycopeptides (vancomycin and teicoplanin) are high-molecular-weightantibiotics that bind to the terminal D-alanine–D-alanine component of the stempeptide while the subunits are external to the cell membrane but still linked to thelipid carrier. This binding sterically inhibits the addition of subunits to thepeptidoglycan backbone. β-Lactam Antibiotics β-Lactam antibiotics (penicillins, cephalosporins, carbapenems, andmonobactams; Table 127-2) are characterized by a four-membered β-lactam ringand prevent the cross-linking reaction called transpeptidation. The energy forattaching a peptide cross-bridge from the stem peptide of one peptidoglycansubunit to another is derived from the cleavage of a terminal D-alanine residuefrom the subunit stem peptide. The cross-bridge amino acid is then attached to thepenultimate D-alanine by transpeptidase enzymes. The β-lactam ring of theantibiotic forms an irreversible covalent acyl bond with the transpeptidase enzyme(probably because of the antibiotics steric similarity to the enzymes D-alanine–D-alanine target), preventing the cross-linking reaction. Transpeptidases and similarenzymes involved in cross-linking are called penicillin-binding proteins (PBPs)because they all have active sites that bind β-lactam antibiotics. Table 127-2 Classification of β-Lactam Antibiotics Route of Administration Class Parenteral Oral Penicillins β-Lactamase–susceptible Narrow-spectrum Penicillin G Penicillin V Enteric-active Ampicillin Amoxicillin, ampicillin Enteric-active and Ticarcillin, Noneantipseudomonal piperacillin β-Lactamase–resistant Antistaphylococcal Oxacillin, Cloxacillin, nafcillin dicloxacillin Combined with β- Ticarcillin plus ...