Добавил:
Upload Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз: Предмет: Файл:
Color_Atlas_of_Pharmacology_3rdEd.pdf
Скачиваний:
32
Добавлен:
27.02.2016
Размер:
12.08 Mб
Скачать

278 Antibacterial Drugs

Inhibitors of Protein Synthesis

Protein synthesis means translation into a peptide chain of a genetic message first transcribed into mRNA. Amino acid (AA) assembly occurs at the ribosome. Delivery of amino acidstomRNAinvolvesdifferenttransferRNA molecules (tRNA), each of which binds a specific AA. Each tRNA bears an “anticodon” nucleobase triplet that is complementary to a particular mRNA coding unit (codon, consisting of three nucleobases).

Incorporation of an AA normally involves the following steps (A):

1.The ribosome “focuses” two codons on mRNA; one (at the left) has bound its tRNA–AA complex, the AA having already been added to the peptide chain; the other (at the right) is ready to receive the next tRNA–AA complex.

2.Afterthelatterattaches,theAAsof thetwo adjacent complexes are linked by the action of the enzyme peptide synthetase (peptidyltransferase). Concurrently, AA and tRNA of the left complex disengage.

3.The left tRNA dissociates from mRNA. The ribosome can advance along the mRNA strand and focus on the next codon.

4.Consequently, the right tRNA–AA complex

shifts to the left, allowing the next complex to be bound at the right.

These individual steps are susceptible to inhibition by antibiotics of different groups. The examples shown originate primarily from Streptomyces species, some of the aminoglycosides also being derived from Micromonospora bacteria.1

1a. Tetracyclines inhibit the binding of tRNA–AA complexes. Their action is bacteriostatic and affects a broad spectrum of pathogens.

_

1 A note on spelling: the termination -mycin denotes origin from Streptomyces species; -mi- cin (e.g., gentamicin) denotes origin from Micromonospora species.

1b. Aminoglycosides induce the binding of “wrong” tRNA–AA complexes, resulting in synthesis of false proteins. Aminoglycosides are bactericidal. Their activity spectrum encompasses mainly Gram-negative organisms. Streptomycin and kanamycin are used predominantly in the treatment of tuberculosis.

2.Chloramphenicol inhibits peptide synthetase. It has bacteriostatic activity against a broad spectrum of pathogens. The chemically simple molecule is now produced synthetically.

3.Macrolides suppresses advancement of the ribosome. Their action is predominantly bacteriostatic and is directed mainly against Gram-positive organisms. Intracellular germs such as chlamydias and mycoplasms are also affected. Macrolides are effective orally. The prototype of this group is erythromycin. Among other uses, it is suitable as a substitute in allergy or resistance to penicillin. Clarithromycin, roxithromycin and azithromycin are erythromycin derivatives with similar activity; however, their elimination is slower and, therefore, permits reduction in dosage and less frequent administration. Gastrointestinal disturbances may occur. Because of inhibition of CYP isozymes (CYP3A4) the risk of drug interactions is present. Telithromycin is a semisynthetic macrolide with a modified structure (“ketolide”). It has a different pattern of resistance that is attributed to interaction with an additional ribosomal binding site.

Lincosamides. Clindamycin has antibacterial activity similar to that of erythromycin. It exerts a bacteriostatic effect mainly on Gram-positive aerobic, as well as on anaerobic pathogens. Clindamycin is a semisynthetic chloro analogue of lincomycin, which derives from a Streptomyces species. Taken orally, clindamycin is better absorbed than lincomycin, has greater antibacterial ef cacy and is thus preferred. Both penetrate well into bone tissue.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Inhibitors of Protein Synthesis

279

A. Protein synthesis and modes of action of antibacterial drugs

 

 

 

 

 

 

 

 

 

 

 

 

H3C

 

CH3

 

 

 

 

 

H3C

HO

 

N

 

 

 

 

 

mRNA

 

 

 

 

 

 

OH

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

C

 

 

 

 

 

OH O

HO

O

 

 

 

Ribosome

 

Tetracyclines

 

H

 

NH2

 

 

 

Doxycycline

 

 

 

 

 

 

 

 

 

Amino acid

 

NH2

OH

 

HO

NH2

 

tRNA

 

 

 

 

 

 

 

 

 

Insertion of

HO

O

 

 

O

 

 

OH

 

 

 

 

 

O

 

 

incorrect

 

O

 

 

 

 

 

 

 

amino acid

H2C

H2N

 

 

NH2

CH2OH

Peptide chain

Aminoglycosides

NH2

Tobramycin

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OH

 

 

 

 

 

 

 

 

O2N

 

CH

CH

CH2

OH

 

 

 

 

 

 

NH

 

 

 

 

 

 

 

 

O

C

CHCl2

 

 

 

 

 

 

 

 

 

 

 

 

Chloramphenicol

 

 

Chloramphenicol

 

 

 

 

 

 

 

 

 

Peptide

 

 

 

 

 

 

 

 

 

 

synthetase

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3

 

 

 

H3C

 

 

 

 

 

 

 

HO

 

N

CH3

 

 

 

 

 

 

 

 

 

 

 

H3C

O

CH3 O

 

 

 

 

 

 

 

 

OH OH

 

H3C

O

 

 

 

 

H3C

OH

 

 

O CH3

 

 

 

O

CH3

 

 

 

 

 

 

 

H3C H2C

O

 

H3C OH

 

 

 

O

 

 

 

 

 

 

CH3

 

O

 

 

 

 

 

Macrolides

 

 

 

 

 

 

CH3

 

 

 

 

 

Erythromycin

 

 

 

 

 

Streptomyces species

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

280 Antibacterial Drugs

4. Oxazolidinones, such as linezolide, are a newly discovered drug group (p.281). They inhibit initiation of synthesis of a new peptide strand at the point where ribosome, mRNA, and the “start-tRNA–AA” complex aggregate. Oxazolidinones exert a bacteriostatic effect on Gram-positive bacteria. Since bone marrow depression has been reported, hematological monitoring is necessary.

Tetracyclines are absorbed from the gastrointestinal tract to differing degrees, depending on the substance, absorption being nearly complete for doxycycline and minocycline. Intravenous injection is rarely needed (rolitetracycline is available only for i.v. administration). The most common unwanted effect is gastrointestinal upset (nausea, vomiting, diarrhea, etc.) due to (1) a direct mucosal irritant action of these substances and

(2) damage to the natural bacterial gut flora (broad-spectrum antibiotics) allowing colonization by pathogenic organisms, including Candida fungi. Concurrent ingestion of antacids or milk would, however, be inappropriate because tetracyclines form insoluble complexes with plurivalent cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+) resulting in their inactivation; that is, absorbability, antibacterial activity, and local irritant action are abolished. The ability to chelate Ca2+ accounts for the propensity of tetracyclines to accumulate in growing teeth and bones. As a result, there occurs an irreversible yellowbrown discoloration of teeth and a reversible inhibition of bone growth. Because of these adverse effects, tetracycline should not be given after the second month of pregnancy and not prescribed to children aged 8 years and under. Other adverse effects are increased photosensitivity of the skin and hepatic damage, mainly after i.v. administration.

Chloramphenicol. The broad-spectrum antibiotic chloramphenicol is completely absorbed after oral ingestion. It undergoes even distribution in the body and readily crosses diffusion barriers such as the blood–

brain barrier. Despite these advantageous properties, use of chloramphenicol is only rarely indicated (e.g., in CNS infections) because of the danger of bone marrow damage.

Two types of bone marrow depression can occur: (1) a dose-dependent, toxic, reversible form manifested during therapy, and (2) a frequently fatal form that may occur after a latency of weeks and is not dose-dependent. Owing to high tissue penetrability, the danger of bone marrow depression must be taken into account even after local use (e.g., eye drops).

Aminoglycoside antibiotics consist of glyco- side-linked amino sugars (cf. gentamicin C1a, a constituent of the gentamicin mixture). They contain numerous hydroxyl groups and amino groups that can bind protons. Hence, these compounds are highly polar, poorly membrane permeable and not absorbed enterally. Neomycin and paromomycin are given orally in order to eradicate intestinal bacteria (prior to bowel surgery or for reducing NH3 formation by gut bacteria in hepatic coma). Aminoglycosides for the treatment of serious infections must be injected (e.g., gentamicin, tobramycin, amikacin, netilmicin, sisomycin). In addition, local inlays of a gentamicin-releasing carrier can be used in infections of bone or soft tissues. Aminoglycosides gain access to the bacterial interior via bacterial transport systems. In the kidney, they enter the cells of the proximal tubules via an uptake system for oligopeptides. Tubular cells are susceptible to damage (nephrotoxicity, mostly reversible). In the inner ear, sensory cells of the vestibular apparatus and Corti’s organ may be injured (ototoxicity, in part irreversible).

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Inhibitors of Protein Synthesis

281

A. Aspects of the therapeutic use of tetracyclines, chloramphenicol, and aminoglycosides

Tetracyclines

 

 

 

 

 

 

 

Chloramphenicol

 

 

 

 

 

 

 

 

Advantage:

 

 

 

 

 

 

 

 

good penetration

 

 

 

 

 

 

 

 

through barriers

Inactivation by

 

 

 

 

 

 

 

 

 

chelation of

 

 

 

 

 

 

 

 

 

Ca2+, Al3+ etc.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Disadvantage:

 

 

 

 

 

 

 

 

bone marrow

 

 

 

 

 

 

 

 

toxicity

Irritation of

 

 

 

 

 

 

 

 

 

mucous

 

 

 

 

 

 

 

 

 

membranes

 

 

 

 

 

 

 

Linezolide

 

 

 

 

 

 

 

 

 

 

 

 

formation

 

 

 

 

 

F

O

Absorption

complex

 

 

 

O

N

N

O

Antibacterial

 

 

 

 

 

 

H3C C N

effect on

 

 

 

 

 

 

gut flora

 

 

 

 

 

 

 

O

H

 

Aminoglycoside

 

 

 

CH3

 

 

 

 

 

 

H+

 

 

 

 

 

 

 

 

 

 

H+NH

 

 

 

 

 

 

NH2

HO

 

 

 

 

 

e.g.,

 

 

OH

 

OH

 

 

 

 

 

O

O

 

 

 

 

 

 

 

 

 

 

 

 

neomycin

 

 

CH3

 

 

 

 

 

O

 

O

 

 

 

 

 

H2C

H2N

NH2

 

 

 

 

 

 

 

HNH+ 2

H+

H+

 

 

 

 

 

 

 

Gentamicin C1a

 

 

 

 

 

 

 

 

 

 

 

 

Cochlear and

 

 

 

 

 

 

 

 

vestibular

 

High hydrophilicity

 

 

 

 

ototoxicity

 

no passive diffusion

 

H+

 

 

 

 

 

through membranes,

 

H+

 

 

 

 

therefore parenteral

 

H+

 

 

 

 

use

 

 

 

 

 

 

 

 

 

 

Basic

 

 

 

 

 

 

 

 

oligopeptides

 

 

 

 

 

 

Transport system

 

 

 

 

 

 

 

 

Nephro-

 

 

 

 

Bacterium

 

 

 

toxicity

 

 

 

No absorption

 

 

 

 

 

 

 

 

 

“bowel sterilization”

 

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Соседние файлы в предмете [НЕСОРТИРОВАННОЕ]