Inhibitors of Bacterial Protein Synthesis



Inhibitors of Bacterial Protein Synthesis



Classification of Inhibitors of Bacterial Protein Synthesis




aAlso amikacin and tobramycin (TOBREX).




Overview


After the introduction of penicillin, scientists began an extensive search for antibiotics that could inhibit penicillin-resistant bacteria. A number of Streptomyces species were isolated from soil samples collected from all over the world, and these species eventually yielded several new classes of antibiotics, including the aminoglycosides, tetracyclines, and macrolides. Streptomycin, an aminoglycoside, was the first new antibiotic to be introduced through these efforts (Box 39-1).



Box 39-1   A Case of Abscess and Drainage




Case Discussion


The number of community-acquired MRSA infections has increased dramatically in the past 5 years. MRSA is now the most common pathogen isolated from skin and soft tissue infections in emergency departments. These infections may be managed by incision and drainage if systemic signs such as fever and tachycardia are absent. The optimal antibiotic therapy for these infections has not been established, but clindamycin, trimethoprim-sulfamethoxazole, and other oral agents are usually effective (see Table 39-4). Clindamycin susceptibility test results may be misleading because of the occurrence of inducible clindamycin resistance expressed by the erm gene (see text). The D-zone test can be used to detect this form of resistance. This test result is positive if a D-shaped or blunted area of inhibition surrounds the clindamycin disk on a culture of the clinical isolate. In the present case, the D-zone test result was negative, and the patient was effectively treated with clindamycin.



Bacterial Protein Synthesis


Several classes of antibiotics act by selectively blocking one or more steps in the protein synthesis of bacteria, which are prokaryotes, while having relatively little effect on the protein synthesis of mammals and other eukaryotes. The selectivity for bacterial protein synthesis is a result of differences in the structure and function of ribosomes in prokaryotic versus eukaryotic cells.


Each ribosome has two subunits. The ribosome in prokaryotes is composed of a 30S subunit and a 50S subunit (with S denoting the Svedberg unit of flotation, which forms the basis for the separation and isolation of ribosomal subunits from cell homogenates). In contrast, the ribosome in eukaryotes is composed of a 40S and a 60S subunit, and the proteins that initiate and carry out translation of messenger RNA (mRNA) in eukaryotic systems are more complex and function differently than the proteins of bacterial systems.


The basic steps in bacterial protein synthesis are illustrated in Figure 39-1. These steps include the binding of aminoacyl transfer RNA (tRNA) to the ribosome, the formation of a peptide bond, and translocation. Aminoacyl tRNA binds to the 30S ribosomal subunit, whereas peptide bond formation and translocation involve components of the 50S ribosomal subunit.


image
FIGURE 39-1 Bacterial protein synthesis and sites of drug action. The bacterial ribosome is composed of a 30S subunit and a 50S subunit. The steps in protein synthesis and translation of messenger RNA (mRNA) include the binding of aminoacyl transfer RNA (tRNA) to the ribosome, the formation of a peptide bond, and translocation. A, Under normal circumstances, the nascent peptide is attached to the ribosome at the peptidyl site (P site), and the next aminoacyl tRNA binds to the acceptor or aminoacyl site (A site). Tetracyclines block aminoacyl tRNA from binding to the A site. Aminoglycosides cause misreading of the genetic code, which leads to binding of the wrong aminoacyl tRNA and insertion of the wrong amino acid into the nascent peptide. B, Macrolides, chloramphenicol, and dalfopristin block peptidyl transferase, the enzyme that catalyzes the formation of a peptide bond between the nascent peptide and the amino acid attached to the A site. C, Macrolides and clindamycin block the translocation step in which the nascent peptide is transferred from the A site to the P site after the formation of a new peptide bond.


Sites of Drug Action


As shown in Figure 39-1, each type of antibiotic discussed in this chapter acts at a specific site on the ribosome to inhibit one or more steps in protein synthesis. Tetracyclines and aminoglycosides act at the 30S ribosomal subunit. Macrolides, chloramphenicol, dalfopristin, and clindamycin act at the 50S ribosomal subunit.


Tetracyclines competitively block binding of tRNA to the 30S subunit and thereby prevent the addition of new amino acids to the growing peptide chain. This reversibility of this effect accounts for the bacteriostatic action of tetracyclines.


Aminoglycosides also bind to the 30S subunit, where they interfere with the initiation of protein synthesis and cause misreading of the genetic code so that the wrong amino acid is inserted into the protein structure. These irreversible actions account for the bactericidal effects of these antibiotics.


Macrolides, chloramphenicol, and dalfopristin block peptidyl transferase, the enzyme that catalyzes the formation of a peptide bond between the new amino acid and the nascent peptide. Macrolides and clindamycin prevent translocation of the nascent peptide from the acceptor or aminoacyl site (A site) to the peptidyl site (P site) on the ribosome, which in turn prevents binding of the next aminoacyl tRNA to the ribosome.



Drugs That Affect the 30S Ribosomal Subunit


Aminoglycosides


The aminoglycosides include amikacin, gentamicin, neomycin, streptomycin, and tobramycin. The properties and major clinical uses of these drugs are compared in Tables 39-1 and 39-2.



TABLE 39-1


Pharmacokinetic Properties of Bacterial Protein Synthesis Inhibitors*































































































































DRUG ROUTE OF ADMINISTRATION ORAL BIOAVAILABILITY ELIMINATION HALF-LIFE (HOURS) PRIMARY ROUTE OF ELIMINATION
Aminoglycoside Antibiotics
Amikacin IV NA 2.5 Renal excretion
Gentamicin IV or topical NA 1.5 Renal excretion
Neomycin Topical NA NA NA
Streptomycin IM NA 2 Renal excretion
Tobramycin IV or topical NA 2.5 Renal excretion
Tetracycline and Related Antibiotics
Doxycycline Oral or IV 90% 20 Fecal and renal excretion
Minocycline Oral or IV 95% 20 Biliary and renal excretion
Tetracycline Oral or IV 70% 10 Renal excretion
Tigecycline IV NA 40 Biliary, fecal, and renal excretion
Macrolide and Ketolide Antibiotics
Azithromycin Oral or IV 37% 12 Biliary excretion
Clarithromycin Oral 62% 5 Biliary and renal excretion
Erythromycin Oral, IV, or topical 35% ± 25% 2 Biliary excretion
Telithromycin Oral 60% 10 Biliary and renal excretion
Other Antibiotics
Chloramphenicol Oral, IV, or topical 95% 3 Hepatic metabolism; renal excretion
Clindamycin Oral, IV, or topical 95% 2.5 Hepatic metabolism; renal, biliary, and fecal excretion
Linezolid Oral or IV 100% 6 Hepatic metabolism; renal excretion
Mupirocin Topical NA NA NA
Quinupristin-dalfopristin IV NA 0.8 and 0.4† Hepatic metabolism; biliary excretion


image


IM, Intramuscular; IV, intravenous; NA, not applicable.


*Values shown are the mean of values reported in the literature.


†The half-lives for quinupristin and dalfopristin are 0.8 and 0.4 hours, respectively. The drugs are given in combination.



TABLE 39-2


Major Clinical Uses of Selected Bacterial Protein Synthesis Inhibitors














































DRUG INFECTIONS
Streptomycin Plague, tularemia, drug-resistant tuberculosis
Gentamicin, tobramycin, and amikacin Infective endocarditis; infections with aerobic gram-negative bacilli, including Pseudomonas aeruginosa
Tetracycline antibiotics Lyme disease, Rocky Mountain spotted fever, ehrlichiosis, granuloma inguinale, brucellosis, cholera, relapsing fever, peptic ulcer disease from Helicobacter pylori, chlamydial urethritis, acne, MRSA
Tigecycline Skin and soft tissue infections with MRSA; intraabdominal infections with various organisms; community-acquired pneumonia
Erythromycin Respiratory tract infections with streptococci, pneumococci, Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydia pneumoniae
Azithromycin, clarithromycin Respiratory tract infections with organisms sensitive to erythromycin, Haemophilus influenzae, Moraxella catarrhalis, Mycobacterium avium-intracellulare
Clarithromycin Peptic ulcer disease from H. pylori
Telithromycin Community-acquired pneumonia from pneumococci, Legionella, Chlamydia, and other organisms
Chloramphenicol Meningitis, brain abscess
Clindamycin Streptococcal, staphylococcal, and anaerobic infections
Quinupristin-dalfopristin Skin and soft tissue infections with Staphylococcus aureus or Streptococcus pyogenes; infections with Enterococcus faecium
Linezolid Infections with vancomycin-resistant E. faecium, streptococci, and methicillin-resistant staphylococci
Mupirocin Impetigo from streptococci, staphylococci; eradication of nasal colonization of MRSA

MRSA, Methicillin-resistant Staphylococcus aureus.



Chemistry and Pharmacokinetics


Aminoglycoside antibiotics are composed of amino sugars linked through glycosidic bonds. The amino groups are highly basic and become extensively protonated and ionized in body fluids. For this reason, the aminoglycosides are poorly absorbed from the gut and must be administered parenterally for the treatment of systemic infections. Occasionally they are administered orally to treat gastrointestinal infections such as neonatal necrotizing enterocolitis. They are also administered topically to treat infections of the skin, mucous membranes, and ocular tissues.


Because of their highly ionized nature, aminoglycosides do not penetrate tissue cells significantly, and their volumes of distribution are similar to the extracellular fluid volume. Aminoglycosides also have poor penetration of the meninges, even when the meninges are inflamed, and intrathecal administration may be required to treat meningitis.


The aminoglycosides are not metabolized. They are excreted primarily by renal glomerular filtration, with little tubular reabsorption. The renal clearance of aminoglycosides is approximately equal to the creatinine clearance, because creatinine is also filtered at the glomerulus but is not secreted or reabsorbed significantly by the tubules. Because the clearance of aminoglycosides is proportional to the glomerular filtration rate, the dosage of aminoglycosides must be reduced in patients with renal impairment. In most cases this is accomplished by increasing the interval between doses.


The plasma concentrations of aminoglycosides are routinely measured to ensure adequate dosage and to minimize toxicity. The peak concentration is found about 30 minutes after completing an intravenous infusion of an aminoglycoside, whereas the trough concentration is found immediately before administration of the next dose. Optimal peak and trough concentrations have been established and can be used to guide dosage adjustments for individuals receiving the standard regimen of three daily doses given at 8-hour intervals. For example, therapeutic concentrations of gentamicin and tobramycin are usually between 4 and 8 mg/L. A peak concentration above 12 mg/L or a trough concentration above 2 mg/L is considered toxic and indicates the need to reduce the dosage of gentamicin or tobramycin. Therapeutic concentrations of amikacin are between 16 and 32 mg/L, and the toxic peak and trough concentrations are above 35 mg/L and above 10 mg/L, respectively.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Inhibitors of Bacterial Protein Synthesis

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