Classification of penicillins

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Chapter: Medicinal Chemistry : Antibiotics

I. Penicillinase-susceptible penicillins II. Penicillinase-resistant penicillins III. Aminopenicillins IV. Antipseudomonal penicillins (Carboxy Penicillins) V. Ureidopenicillins VI. Miscellaneous penicillins


I. Penicillinase-susceptible penicillins

The general impact on antibacterial activity is as follows:

·Good gram-positive potency against susceptible Staphylococci and Streptococci

·Useful against some gram-positive cocci

·Not effective against gram-negative bacilli


II. Penicillinase-resistant penicillins

General impact on antibacterial activity is as follows:

·Decreased susceptibility to many penicillinase.

·Active against microrganisms, resistant to early penicillin.

·Oxacillins offer good oral activity.


III. Aminopenicillins

General impact on antibacterial activity is as follows:

·Extended spectrum of activity against some gram-negative bacteria and retention of gram-positive potency

·Ineffective against Pseudomonas aeruginosa


IV. Antipseudomonal penicillins (Carboxy Penicillins)


V. Ureidopenicillins

General impact on antibacterial activity is as follows:

·Enhanced spectrum of activity against P. aeruginosa and expanded activity against Klebsiella.

·Good potency against gram-positive bacteria, but generally not effective against penicillinase producers.

·Good pharmacokinetic profile.

·Good activity against Escherichia coli, Klebsiella, Shigella, Salmonella, and many other resistant species.


VI. Miscellaneous penicillins

The chemical degradation of penicillins is depicted in Figure 4.1

Inactivation of penicillins by acids, bases, and β-lactamases is as follows:

·The penicillins are very reactive due to the strained amide bond in the fused β-lactum of the nucleus.

·Penicillins undergo a complex series of reactions leading to a variety of inactive degradation products.

·They are extremely susceptible to nucleophilic attack by water or hydroxide ion to form the penicilloic acid. β-Lactamses also cleave the β-lactam ring to give penicilloic acid with a consequent loss of antibacterial activity.

·In strongly acidic solutions (pH < 3), penicillin is protonated at the β-lactam nitrogen, and this is followed by nucleophillic attack of the acyl oxygen atom on the β-lactam carbonyl carbon. The subsequent opening of the β-lactam ring destabilizes the thiazoline ring, which opens to form penicillenic acid that degrades into two major products penicillamine and penilloic acid. A third product, penicilloaldehyde is also formed.

·Acid-catalyzed degradation in the stomach contributes in a major way to the poor oral absorption of penicillin. Thus, efforts to obtain penicillins with improved pharmacokinetic and microbiologic properties have sought to find acyl functionalities that would minimize sensitivity of the β-lactam ring to acid hydrolysis and at the same time, maintain antibacterial activity.

·Substitution of an electron-withdrawing group for the α-position of the benzyl penicillin has stabilized the penicillin to acid catalyzed hydrolysis. The increased stability imparted by such electron-withdrawing groups has been attributed to a decrease in the reactivity of the side chain amide carbonyl oxygen atom towards participation in β-lactam ring opening to form the penicillenic acid.

Mode of action: The cell wall of bacteria is essential for the normal growth and development. Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanism for stability by virtue of its highly cross-linked lattice-wise structure. The peptidoglycan is composed of glycan chains, which are linear strands of two alternating amino sugars (N-acetyl glucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains of an enzyme, transpeptidase. Penicillins inhibit the transpeptidase activity to the synthesis of cell walls. They also block cleavage of terminal D-alanine during the cell wall synthesis. The biosynthesis of peptidoglycan involves three stages (Fig. 4.2).

 B-lactam antibiotics inhibit the last step in peptidoglycan synthesis. The transpeptidase enzyme that contains serine is probably acylated by β-lactam antibiotics with the cleavage of -CO-N-bond of the βlactam ring. This renders the enzyme inoperative and inhibits peptidoglycan synthesis.

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