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270 Antibacterial Drugs

Inhibitors of Cell Wall Synthesis

In most bacteria, a cell wall surrounds the cell like a rigid shell that protects against noxious outside influences and prevents rupture of the plasma membrane from a high internal osmotic pressure. The structural stability of the cell wall is due mainly to the murein (peptidoglycan) lattice. This consists of basic building blocks linked together to form a large macromolecule. Each basic unit contains the two linked aminosugars N-acetylglucosamine and N-acetyl- muramic acid; the latter bears a peptide chain. The building blocks are synthesized in the bacterium, transported outward through the cell membrane, and assembled as illustrated schematically. The enzyme transpeptidase cross-links the peptide chains of adjacent aminosugar chains.

Inhibitors of cell wall synthesis are suitable antibacterial agents because animal, including human, cells lack a cell wall. These agents exert a bactericidal action on growing or multiplying germs. Members of this class include β-lactam antibiotics such as the penicillins and cephalosporins, in addition to bacitracin and vancomycin.

Penicillins (A). The parent substance of this group is penicillin G (benzylpenicillin). It is obtained from cultures of mold fungi, originally from Penicillium notatum. Penicillin G contains the basic structure common to all penicillins, 6-aminopenicillanic acid (6- APA; p.273) comprising a thiazolidine and a 4-membered β-lactam ring. 6-APA itself lacks antibacterial activity. Penicillins disrupt cell wall synthesis by inhibiting transpeptidase. When bacteria are in their growth and replication phase, penicillins are bactericidal; as a result of cell wall defects, the bacteria swell and burst.

Penicillins are generally well tolerated; with penicillin G, the daily dose can range from approx. 0.6 g i.m. (= 106 international units, 1 Mega IU [MIU]) to 60 g by infusion. The most important adverse effects are due

to hypersensitivity (incidence up to 5%), with manifestations ranging from skin eruptions to anaphylactic shock (in less than 0.05% of patients). Known penicillin allergy is a contraindication for these drugs. Because of an increased risk of sensitization, penicillins must not be used locally. Neurotoxic effects, mostly convulsions due to GABA antagonism, may occur if the brain is exposed to extremely high concentrations, e.g., after rapid i.v. injection of a large dose or intrathecal injection.

Penicillin G undergoes rapid renal elimination mainly in unchanged form (plasma t½ ~ 0.5 hours). The duration of the effect can be prolonged by:

1.Use of higher doses, enabling plasma levels to remain above the minimally effective antibacterial concentration.

2.Combination with probenecid. Renal elimination of penicillin occurs chiefly via the anion (acid)-secretory system of the proximal tubule (–COOH of 6-APA). The acid probenecid (p.326) competes for this route and thus retards elimination of penicillin.

3.Intramuscular administration in depot form. In its anionic form (–COO) penicillin G forms poorly water-soluble salts with substances containing a positively charged amino group (procaine; clemizole, an antihistaminic; benzathine, dicationic). Depending on the substance, release of penicillin from the depot occurs over a variable interval.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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

Inhibitors of Cell Wall Synthesis

271

A.Penicillin G: structure and origin; mode of action of penicillins; methods for prolonging duration of action

Cell wall

Cell membrane

Bacterium

 

 

 

 

Cross-linked by

 

 

 

 

 

transpeptidase

Inhibition of

 

 

Amino acid

 

 

 

chain

 

cell wall synthesis

 

 

Cell wall

 

 

Sugar

 

 

 

 

building block

 

O

 

 

Human

 

C 2

C NH

 

 

 

Antibody

S

CH3

 

 

H

 

 

 

 

 

 

 

 

 

N

 

CH3

Penicillin

 

Penicillin G

O

 

allergy

 

COOH

 

 

 

 

 

 

Neurotoxicity

Fungus

at very

Penicillium notatum

high dosage

Plasma concentration

Penicillin

3 x Dose

Minimal bactericidal concentration

Probenecid

Anion secretory system

Time

Increasing the dose

Combination with probenecid

 

 

Procaine

+

-

 

 

 

 

 

 

 

 

 

 

 

Penicillin

 

 

 

 

 

 

Clemizole

+

 

 

 

~1

-

 

 

 

Penicillin

 

 

 

 

 

 

 

 

 

(d)

 

 

 

 

 

 

+

actionof

~2

 

 

 

 

+

Benzathine

-

 

 

 

Duration

 

 

 

Penicillins

 

 

~7–28

 

 

 

 

 

2

 

 

 

 

Depot preparations

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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

272 Antibacterial Drugs

Although very well tolerated, penicillin G has disadvantages (A) that limit its therapeutic usefulness: (1) it is inactivated by gastric acid, which cleaves the β-lactam ring, necessitating parenteral administration. (2) The β-lactam ring can also be opened by bacterial enzymes (β-lactamases); in particular, penicillinase, which can be produced by staphylococcal strains, renders them resistant to penicillin G. (3) The antibacterial spectrum is narrow; although it encompasses many Gram-positive bacteria, Gramnegative cocci, and spirochetes, many Gramnegative pathogens are unaffected.

Derivatives with a different substituent on 6-APA possess advantages (B):

1.Acid resistance permits oral administration, provided that enteral absorption is possible. All derivatives shown in (B) can be given orally. Penicillin V (phenoxymethylpenicillin) exhibits antibacterial properties similar to those of penicillin G.

2.Owing to their penicillinase resistance, isoxazolylpenicillins (oxacillin, dicloxacillin, floxacillin) are suitable for the (oral) treatment of infections caused by penicillin- ase-producing staphylococci.

3.Extended-activity spectrum: The aminopenicillin amoxicillin is active against many Gram-negative organisms, e.g., colibacteria or Salmonella typhi. It can be protected from destruction by penicillinase by combination with inhibitors of

penicillinase (clavulanic acid, sulbactam, tazobactam).

The structurally close congener ampicillin (no 4-hydroxy group) has a similar activity spectrum. However, because it is poorly absorbed (<50%) and therefore causes more extensive damage to the gut microbial flora (side effect: diarrhea), it should be given only by injection.

A still broader spectrum (including pseudomonad bacteria) is shown by carboxypenicillins (carbenicillin, ticarcillin) and acylaminopenicillins (mezclocillin, azlocillin, piperacillin). These substances are neither acidstable nor penicillinase-resistant.

Cephalosporins (C). These β-lactam antibiotics are also fungal products and have bactericidal activity due to inhibition of transpeptidase. Their shared basic structure is 7- aminocephalosporanic acid, as exemplified by cefalexin (gray rectangle). Cephalosporins are acid-stable, but many are poorly absorbed. Because they must be given parenterally, most—including those with high activity—are used only in clinical settings. A few, e.g., cefalexin, are suitable for oral use. Cephalosporins are penicillinase-resistant but cephalosporinase-forming organisms do exist. However, some derivatives are also resistant to this β-lactamase. Cephalosporins are broad-spectrum antibacterials. Newer derivatives (e.g., cefotaxime, cefmenoxin, ceftriaxone, ceftazidime) are also effective against pathogens resistant to various other antibacterials. Cephalosporins are mostly well tolerated. All can cause allergic reactions, some also renal injury, alcohol intolerance, and bleeding (vitamin K antagonism).

Other inhibitors of cell wall synthesis. Bacitracin and vancomycin interfere with the transport of peptidoglycans through the cytoplasmic membrane and are only active against Gram-positive bacteria. Bacitracin is a polypeptide mixture; it is markedly nephrotoxic and is used only topically. Vancomycin is a glycopeptide and the drug of choice for the (oral) treatment of bowel inflammations occurring as a complication of antibiotic therapy (pseudomembranous enterocolitis caused by Clostridium dif cile). It is not absorbed. Infections with Gram-posi- tive cocci that are resistant against better tolerated drugs can also be treated with vancomycin given systemically. This entails an increased risk of ototoxicity (hearing loss, tinnitus) or vestibular toxicity (vertigo, ataxia, and nystagmus).

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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

Inhibitors of Cell Wall Synthesis

273

A. Disadvantages of penicillin G

 

 

 

 

 

 

 

 

 

 

 

 

 

 

6-Aminopenicillanic acid

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH2

C

NH

S

CH3

Salmonella typhi

 

 

 

 

active

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

N

CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

COOH

 

 

 

 

 

 

 

 

Not

 

 

 

 

 

 

 

 

 

 

 

 

 

negative

Penicillin G

 

 

 

 

 

 

E. coli

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gram

-

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Acid sensitivity

 

 

 

 

Penicillinase

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

sensitivity

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Treponema

 

 

 

 

 

 

Gonococci

 

 

 

 

 

 

 

 

pallidum

 

 

 

 

 

 

 

 

 

 

H+Cl-

 

Penicillinase

actionspectrum

 

 

 

positive

 

 

 

 

 

 

 

 

 

 

 

Active

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gram

-

 

 

 

Pneumococci

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Narrow-

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Staphylococci

 

 

 

 

 

 

 

Streptococci

B. Derivatives of penicillin G

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Concentration needed

 

 

 

 

 

 

Acid

Penicillinase

Spectrum

 

 

 

to inhibit penicillin G-

 

 

 

 

 

 

 

 

 

 

 

 

 

sensitive bacteria

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

CH2 C

NH

S

CH3

Resis-

Sensitive

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Penicillin V

O

N

CH3

tant

 

 

Narrow

 

 

 

 

 

 

 

 

 

COOH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

C NH

 

 

 

 

Resis-

Resistant

 

 

 

 

 

 

 

 

 

O

S

CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

tant

 

 

 

 

 

 

 

 

 

 

CH3

 

N

CH3

 

 

 

 

Narrow

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Oxacillin O

COOH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

HO

CH C

NH

S

CH3

Resis-

Sensitive

 

 

 

 

 

 

 

 

 

 

NH2

 

tant

 

 

 

 

 

 

 

 

 

 

 

 

N

CH3

 

 

Broad

 

 

 

 

 

 

 

Amoxicillin

O

 

 

 

 

 

 

 

 

 

 

COOH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

C. Cephalosporin

 

 

 

 

O

 

 

 

 

 

CH C

NH

S

 

Resistant,

 

 

 

 

 

NH2

 

 

Resis-

 

N

 

but sensitive to

 

Cefalexin

O

CH3

tant

cephalosporinase

Broad

 

COOH

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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

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