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Chapter 21 Antimicrobial Medications

Aminoglycosides

Block the initiation of translation and causes the misreading of mRNA

Tetracyclines

Block the attachment of tRNA to the ribosome

Streptogramins

Each interferes with a distinct step of protein synthesis

Aminoglycosides

Block the initiation of translation and causes the misreading of mRNA

Macrolides

Prevent the continuation of protein synthesis

Chloramphenicol

Prevents peptide bonds from being formed

Figure 21.7 Antibacterial Medications that Inhibit Prokaryotic Protein Synthesis These medications bind to the 70S ribosome.

Macrolides

Prevent the continuation of protein synthesis

Chloramphenicol

Prevents peptide bonds from being formed

Lincosamides

Prevent the continuation of protein synthesis

Oxazolidinones

Interfere with the initiation of protein synthesis

Figure 21.7 Antibacterial Medications that Inhibit Prokaryotic Protein Synthesis These medications bind to the 70S ribosome.

structure of the prokaryotic 70S ribosome, which is composed of a 30S and a 50S subunit, is different enough from the eukary-otic 80S ribosome to make it a suitable target for selective toxicity. The mitochondria of eukaryotic cells also have 70S ribosomes, however, which may partially account for the toxicity of some of these drugs. ■ ribosome structure, p. 66 ■ protein synthesis, p. 175

The major classes of antibiotics that inhibit protein synthesis are the aminoglycosides, the tetracyclines, and the macrolides. Others include the lincosamides and chloramphenicol. Of these, only the aminoglycosides are bactericidal; the others are all bacteriostatic. Two classes of drugs that have recently been approved for use in the United States are the oxazolidinones and the streptogramins. A synergistic combination of two streptogramins is bacteriocidal against some organisms.

The Aminoglycosides

The aminoglycosides irreversibly bind to the 30S ribosomal subunit, causing it to distort and malfunction. This blocks the initiation of translation and causes misreading of mRNA by ribosomes that have already passed the initiation step. Aminoglycosides are actively transported into bacterial cells by a process that requires respiratory metabolism. Consequently, they are generally not effective against anaerobes, enterococci, and streptococci. To extend their spectrum of activity, the aminoglycosides are sometimes used in a synergistic combination with a b-lactam drug. The b-lactam drug interferes with cell wall synthesis, which, in turn, allows the aminoglycoside to more easily enter cells that would otherwise be resistant. Examples of aminoglycosides include streptomycin, gentamicin, tobramycin, and amikacin. Unfortunately, these all can cause severe side effects including hearing loss and kidney damage; consequently, they are generally used only when other alternatives are not available. Recently, a form of tobramycin that can be administered through inhalation rather than intravenously was developed, making treatment of lung infections in cystic fibrosis patients caused by Pseudomonas aeruginosa safer and more effective. Another aminoglycoside, neomycin, is too toxic for systemic use; however, it is a common ingredient in non-prescription topical ointments. ■ active transport, p. 56

The Tetracyclines

The tetracyclines reversibly bind to the 30S ribosomal subunit, blocking the attachment of tRNA to the ribosome and preventing the continuation of protein synthesis. These drugs are actively transported into prokaryotic but not animal cells, which effectively concentrates them inside bacteria. This, in part, accounts for their selective toxicity. The tetracyclines are effective against certain Gram-positive and Gram-negative bacteria. The newer tetracyclines such as doxycycline have a longer half-life, allowing less frequent doses. Resistance to the tetracyclines is primarily due to a decrease in their accumulation by the bacterial cell, either by decreased uptake or increased excretion. Tetracyclines can cause discoloration in teeth when used by young children.

The Macrolides

The macrolides reversibly bind to the 50S ribosomal subunit and prevent the continuation of protein synthesis. Macrolides as a group are effective against a variety of bacteria, including many Gram-positive organisms as well as the most common causes of atypical pneumonia ("walking pneumonia"). They often serve as the drug of choice for patients who are allergic to penicillin. Macrolides are not effective against members of the family Enterobacteriaceae, however, because the outer membrane of these organisms excludes the drug. Examples of macrolides include erythromycin, clarithromycin, and azithromycin. Both clarithromycin and azithromycin have a longer half-life than erythromycin, so that they can be taken less frequently. Resistance to all the macrolides can occur through modification of the ribosomal RNA target. Other mechanisms of resistance include the production of an enzyme that chemically modifies the drug and alterations that result in decreased uptake of the drug. ■ walking pneumonia, p. 578

Chloramphenicol

Chloramphenicol binds to the 50S ribosomal subunit, preventing peptide bonds from being formed and, consequently, blocking protein synthesis. Although it is active against a wide range of bacteria, it is generally only used as a last resort for life-threatening infections in order to avoid a rare but lethal side effect. This complication, aplastic anemia, is not related to dose and is characterized by the inability of the body to form white and red blood cells.

The Lincosamides

The lincosamides bind to the 50S ribosomal subunit and prevent the continuation of protein synthesis, inhibiting a variety of Gram-negative and Gram-positive organisms. They are particularly useful for treating infections resulting from intestinal perforation because they inhibit Bacterioides fragilis, a member of normal intestinal flora that is frequently resistant to other antimicrobials. Unfortunately, the risk for people taking lincosamides developing antibiotic-associated colitis is greater than for some other antimicrobials because Clostridium difficile is generally resistant to these drugs. The most commonly used lincosamide is clindamycin.

The Oxazolidinones

The oxazolidinones are a promising new class of antimicrobial drugs. They bind to the 50S ribosomal subunit and interfere with the initiation of protein synthesis. They are effective against a vari

Nester-Anderson-Roberts: I III. Microorganisms and I 21. Antimicrobial I I © The McGraw-Hill

Microbiology, A Human Humans Medications Companies, 2003

Perspective, Fourth Edition ety of Gram-positive bacteria and are useful in treating infections caused by bacteria that are resistant to b-lactam drugs and vancomycin. Because the oxazolidinones have only recently been developed, it is anticipated that resistance will be rare, at least initially. Linezolid is the first drug of this class to be approved for use.

The Streptogramins

Two streptogramins, quinupristin and dalfopristin, are administered together in a recently approved medication called Synercid®. These act as a synergistic combination, binding to two different sites on the 50S ribosomal subunit and inhibiting distinct steps of protein synthesis. Synercid® is effective against a variety of Gram-positive bacteria, including some of those that are resistant to b-lactam drugs and vancomycin.

Antibacterial Medications that Inhibit Nucleic Acid Synthesis

Enzymes that are required for nucleic acid synthesis are the targets of some groups of antimicrobial drugs. These include the fluoroquinolones and the rifamycins.

The Fluoroquinolones

The synthetic drugs called the fluoroquinolones inhibit one or more of a group of enzymes called topoisomerases, which maintain the supercoiling of closed circular DNA within the bacterial cell. One type of topoisomerase, called DNA gyrase or topoiso-merase II, breaks and rejoins strands to relieve the strain caused by the localized unwinding of DNA during replication and transcription. Consequently, inhibition ofthis enzyme prevents these essential cell processes. The fluoroquinolones are bactericidal against a wide variety of bacteria, including both Gram-positive and Gramnegative organisms. Examples of fluoroquinolones include ciprofloxacin and ofloxacin. Acquired resistance is most commonly due to an alteration in the DNA gyrase target. ■ supercoiled DNA, p. 66

The Rifamycins

The rifamycins block prokaryotic RNA polymerase from initiating transcription. Rifampin, which is the most widely used rifamycin, exhibits bactericidal activity against many Grampositive and some Gram-negative bacteria as well as members of the genus Mycobacterium. It is primarily used to treat tuberculosis and Hansen's disease (leprosy) and to prevent meningitis in people who have been exposed to Neisseria meningitidis. In some patients, a reddish-orange pigment appears in urine and tears. Resistance to rifampin develops rapidly and is due to a mutation in the gene that encodes RNA polymerase.

Antibacterial Medications that Inhibit Metabolic Pathways

Relatively few antibacterial medications interfere with metabolic pathways. Among the most useful are the folate inhibitors—sul-fonamides and trimethoprim. These each inhibit different steps in the pathway that leads initially to the synthesis of folic acid and ultimately to the synthesis of a coenzyme required for nucleotide biosynthesis (figure 21.8). Animal cells lack the enzymes in the folic acid synthesis portion of the pathway, which is why folic acid is a dietary requirement. ■ coenzyme, p. 139

21.3 Mechanisms of Action of Antibacterial Drugs

Para-aminobenzoic acid (PABA)

Precursor #1

Para-aminobenzoic acid (PABA)

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Detox Diet Basics

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