Inhibitors of Bacterial Cell Wall Synthesis



Inhibitors of Bacterial Cell Wall Synthesis



Classification of Cell Wall Synthesis Inhibitors














aAlso clavulanate with ticarcillin (TIMENTIN), sulbactam with ampicillin (UNASYN), tazobactam with piperacillin (ZOSYN).


bAlso cefoxitin (MEFOXIN) and cefotetan.


cAlso cefotaxime (CLAFORAN) and ceftazidime (FORTAZ).


dAlso doripenem (DORIBAX), ertapenem (INVANZ), and meropenem (MERREM).




Overview


Several classes of antibiotics inhibit the synthesis of the bacterial cell wall, including the penicillins and cephalosporins. The penicillins were the first antibiotics to be discovered and isolated, and their development inaugurated the modern era of antimicrobial chemotherapy in the 1940s. Despite the growing problem of microbial resistance to these drugs, they have remained one of the most widely used groups of antibiotics for over 60 years. This chapter describes the structure and function of the bacterial cell envelope and the pharmacologic properties and clinical use of the bacterial cell wall inhibitors.



Cell Envelope


Two components of the cell envelope that are found in both gram-positive and gram-negative bacteria are the cytoplasmic membrane and the cell wall. The cell wall is much thicker in gram-positive bacteria than it is in gram-negative bacteria. The envelope of each gram-negative bacterium also has an outer membrane that is not found in other types of bacteria. The cell envelope components are illustrated in Figure 38-1.


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FIGURE 38-1 Comparison of the cell envelopes of gram-positive and gram-negative bacteria. A, The gram-positive bacterium has a thick cell wall but does not have an outer membrane. β-Lactamases are located in the outer portion of the cell wall. Penicillin-binding proteins are found in the cytoplasmic membrane. B, The gram-negative bacterium has a thin cell wall. It also has an outer membrane that contains lipopolysaccharide and protein channels called porins.


Cytoplasmic and Outer Membranes


The cytoplasmic membrane is a trilaminar membrane. It contains various types of transport proteins, which facilitate the uptake of a wide variety of substrates used by bacteria, and it also contains several enzymes required for the synthesis of the cell wall. These enzymes, whose functions are described later in this chapter, are collectively known as penicillin-binding proteins (PBPs).


The outer membrane of gram-negative bacteria is also a trilaminar membrane. It contains species-specific forms of a complex lipopolysaccharide and various types of protein channels called porins. One portion of lipopolysaccharide (the lipid A portion) is the endotoxin responsible for gram-negative sepsis. This endotoxin activates immunologic mechanisms that lead to fever, platelet aggregation, increased vascular permeability, and other adverse effects on tissues. Porins allow ions and other small hydrophilic molecules to pass through the outer membrane, and they are responsible for the entry of several types of antibiotics. Acquired alterations in porin structure can lead to microbial resistance to antibiotics, as is the case with resistance to imipenem.


The bacterial cytoplasmic membrane is the target of two peptide antibiotics, daptomycin and polymyxin. These drugs act directly on the cell membranes to increase membrane permeability and thereby cause the cytoplasmic contents to leak out of the cell. The properties and uses of these antibiotics are discussed in Chapter 40.



Cell Wall


The cell wall consists primarily of peptidoglycan, a polymer constructed from repeating disaccharide units of N–acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). Each disaccharide is attached to others through glycosidic bonds. Each molecule of MurNAc has a peptide containing two molecules of D-alanine and a pentaglycine side chain (Fig. 38-2). The strands of peptidoglycan in the cell wall are cross-linked by a transpeptidase reaction in which the glycine pentapeptide of one strand is attached to the penultimate D-alanine molecule of another strand. During this reaction, the terminal D-alanine is removed.


image
FIGURE 38-2 Sites of action of bacterial cell wall synthesis inhibitors. The bacterial cell wall consists primarily of peptidoglycan, a polymer constructed from repeating disaccharide units of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). Numbers indicate the steps involved in the synthesis of the cell wall of Staphylococcus aureus. In step 1, bactoprenol pyrophosphate (bactoprenol-P-P) is dephosphorylated to regenerate the carrier molecule, bactoprenol phosphate (bactoprenol-P). In step 2, uridine diphosphate-MurNAc (UDP-MurNAc) is added. In steps 3 and 4, UDP-GlcNAc and a glycine pentapeptide (5-Gly-tRNA) are added. In step 5, the disaccharide peptide is transferred to the peptidoglycan growth point. In step 6, the cross-linking of peptidoglycan strands is catalyzed by transpeptidase, a type of penicillin-binding protein. In this reaction a glycine of one strand forms a peptide bond with the penultimate D-alanine of an adjacent strand, and the terminal D-alanine is released. Bacitracin blocks step 1, and β-lactam antibiotics and vancomycin block step 6 by different mechanisms. Fosfomycin (not shown) inhibits enolpyruvyl transferase, the enzyme that catalyzes the condensation of UDP-GlcNAc with phosphoenolpyruvate to synthesize UDP-MurNAc.

The cell wall maintains the shape of the bacterium and protects it from osmotic lysis if it is placed in a hypotonic medium. Without a cell wall, the bacterium is unprotected. This is why inhibition of cell wall synthesis by antimicrobial drugs is usually bactericidal. Because a cell wall is not found in higher organisms, antimicrobial drugs can inhibit its formation without harming host cells. The cell wall is synthesized during bacterial replication, and drugs that inhibit cell wall synthesis are more active against rapidly dividing bacteria than they are against bacteria in the resting or stationary phase. For the same reason, the effectiveness of cell wall inhibitors is sometimes reduced by concurrent administration of bacteriostatic antibiotics that slow the growth of bacteria.



Sites of Drug Action


β-Lactam Drugs


The β-lactam antibiotics bind to a group of bacterial enzymes, the PBPs. These enzymes are anchored in the cytoplasmic membrane and extend into the periplasmic space. The PBPs are responsible for the assembly, maintenance, and regulation of the peptidoglycan portion of the bacterial cell wall. Some of the PBPs have transpeptidase activity, whereas others have carboxypeptidase and transglycosylase activity.


The β-lactam antibiotics form a covalent bond with PBPs and thereby inhibit the catalytic activity of these enzymes. Inhibition of some PBPs prevents elongation or cross-linking of peptidoglycan (see Fig. 38-2), whereas inhibition of other PBPs leads to the bacterium’s autolysis or to its change to a spheroplast or a filamentous form.


Each bacterial species has a unique set of PBPs to which particular β-lactam antibiotics bind with varying affinities. This partly accounts for the variation in the sensitivity of different organisms to β-lactam antibiotics.



Other Drugs


Bacitracin and fosfomycin inhibit cell wall peptidoglycan synthesis by blocking specific steps in the formation of the disaccharide precursor, MurNAc-GlcNAc. As shown in Figure 38-2, bacitracin inhibits the dephosphorylation of bactoprenol pyrophosphate, which is the carrier lipid required for regeneration of bactoprenol phosphate, the active carrier of the disaccharide precursor. Fosfomycin inhibits enolpyruvyl transferase, the enzyme that catalyzes the condensation of uridine diphosphate–GlcNAc (UDP-GlcNAc) with phosphoenolpyruvate to synthesize UDP-MurNAc. Vancomycin binds tightly to the D-alanyl-D-alanine portion of the peptidoglycan precursor and prevents bonding of the penultimate D-alanine to the pentaglycine peptide during cross-linking of peptidoglycan strands.



β-Lactam Antibiotics


The β-lactam antibiotics include penicillins, cephalosporins, carbapenems, and a monobactam antibiotic.



Penicillins


Penicillins were the first antibiotics to be isolated from microorganisms and used to treat bacterial infections. Alexander Fleming is credited with the discovery of penicillin, but he was unable to isolate the substance in sufficient purity and quantity for clinical use. Later, E. B. Chain and H. W. Florey, working in England, obtained enough penicillin to establish its clinical effectiveness. The production of sufficient quantities of penicillin for widespread use around the world was made possible by advances in microbial fermentation technology in the United States.


Penicillins can be grouped according to their antimicrobial activity. Narrow-spectrum penicillins include penicillin G and penicillin V. Penicillinase-resistant (see below) penicillins include dicloxacillin and nafcillin. Extended-spectrum penicillins include amoxicillin, ampicillin, piperacillin, and ticarcillin.



Chemistry


The penicillins consist of a β-lactam ring fused to a thiazolidine ring to which a unique chemical structure (R group) is attached for each antibiotic (Fig. 38-3). The natural penicillins isolated from strains of Penicillium were originally assigned letter designations because their chemical structures could not be identified at that time. Penicillin G and penicillin V are the only natural penicillins still used today, and they are classified as narrow-spectrum drugs. Semisynthetic penicillins are produced by substituting a different R group for the R group of natural penicillin. The penicillinase-resistant penicillins have a large, bulky R group that protects them from hydrolysis by staphylococcal penicillinase, a specific type of bacterial β-lactamase.


image
FIGURE 38-3 Structures of β–lactam drugs. Penicillins contain a β-lactam ring (BLR) and a thiazolidine ring (TR), whereas cephalosporins contain a BLR and a dihydrothiazine ring (DR). β-Lactamases hydrolyze the BLR and convert penicillins to penicilloic acids, which may react with body proteins to form antigens. β-Lactamases convert cephalosporins to inactive cephalosporanic acids (not shown).


Pharmacokinetics


The route of administration of penicillins depends on the stability of the drugs in gastric acid. Acid-stable penicillins, which include amoxicillin, dicloxacillin, and penicillin V, are effective when given orally. In contrast, acid-labile penicillins, which include piperacillin and ticarcillin, must be administered parenterally. Penicillin G has intermediate sensitivity to gastric acid and can be given orally in large doses, but penicillin V has better acid stability and oral bioavailability.


The penicillins are widely distributed to organs and tissues except the central nervous system. Because penicillins readily penetrate the cerebrospinal fluid when the meninges are inflamed (Fig. 38-4), they can be administered intravenously for the treatment of meningitis.


image
FIGURE 38-4 Pharmacokinetics of penicillin G preparations. A, When penicillin G is administered to patients with normal meninges, the concentration in cerebrospinal fluid (CSF) remains low, but when it is administered to patients with meningitis, the CSF concentration is much higher because meningeal inflammation increases meningeal permeability to penicillin G. B, Administration of benzathine penicillin G produces low plasma concentrations of the drug for several weeks. Administration of procaine penicillin G produces higher plasma concentrations for about 24 hours. Probenecid inhibits the renal excretion of penicillin G, prolongs its half-life, and increases its plasma concentrations.

Most penicillin antibiotics are eliminated primarily by active renal tubular secretion and have short half-lives of about 0.5 to 1.3 hours (Table 38-1). A few penicillins (e.g., ampicillin and nafcillin) are excreted primarily in the bile. The renal tubular secretion of penicillins is inhibited by probenecid, a drug that competes with penicillins for the organic acid transporter located in the proximal tubule. Probenecid has been used to slow the excretion and prolong the half-life of penicillin G (see Fig. 38-4).



TABLE 38-1


Pharmacokinetic Properties of Selected Bacterial Cell Wall Synthesis Inhibitors*























































































































































DRUG ROUTE OF ADMINISTRATION ELIMINATION HALF-LIFE (HOURS) PRIMARY ROUTE OF ELIMINATION
β-Lactam Antibiotics
Narrow-Spectrum Penicillins
Penicillin G Oral or parenteral 0.5 Renal (TS)
Penicillin V Oral 1.0 Renal (TS)
Penicillinase-Resistant Penicillins
Dicloxacillin Oral 0.6 Renal (TS)
Nafcillin Oral or parenteral 0.5 Biliary
Extended-Spectrum Penicillins
Amoxicillin Oral 1.0 Renal (TS)
Ampicillin Oral or parenteral 1.0 Renal (TS) and biliary
Piperacillin and ticarcillin Parenteral 1.2 to 1.3 Renal (TS)
First-Generation Cephalosporins
Cefazolin Parenteral 2.0 Renal (TS)
Cephalexin Oral 0.5 Renal (TS)
Second-Generation Cephalosporins
Cefotetan Parenteral 4.0 Renal (TS)
Cefoxitin Parenteral 0.8 Renal (TS)
Cefprozil Oral 1.3 Renal (TS)
Cefuroxime Oral or parenteral 1.7 Renal (TS)
Third-, Fourth-, and Advanced-Generation Cephalosporins
Cefdinir Oral 1.7 Renal (TS)
Cefotaxime Parenteral 1.6† Renal (TS)
Ceftaroline Parenteral (IV) 2.6 Renal (GF)
Ceftazidime Parenteral 1.8 Renal (GF)
Ceftriaxone Parenteral 8.0 Biliary
Cefepime Parenteral 2.0 Metabolized
Monobactam      
Aztreonam Parenteral 1.7 Metabolized
Carbapenems Parenteral 1.0 to 1.2 Renal (TS)
Other Bacterial Cell Wall Synthesis Inhibitors
Bacitracin Topical NA NA
Fosfomycin Oral 6.0 Renal (GF)
Vancomycin Oral or parenteral 6.0 Renal (GF)
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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Inhibitors of Bacterial Cell Wall Synthesis

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