Penicillins

PENICILLINS

Penicillin was the first antibiotic to be used clinically in 1941. It is a miracle that the least toxic drug of its kind was the first to be discovered. It was originally obtained from the fungus Penicillium notatum, but the present source is a high yielding mutant of P. chrysogenum.

Chemistry And Properties

The penicillin nucleus consists of fused thiazolidine and βlactam rings to which side chains are attached through an amide linkage (Fig. 51.1). Penicillin G (PnG),  having a benzyl side chain at R (benzyl penicillin), is the original penicillin used clinically.

The side chain of natural penicillin can be split off by an amidase to produce 6-aminopenicillanic acid. Other side chains can then be attached to it resulting in different semisynthetic penicillins with unique antibacterial activities and different pharmacokinetic profiles.

At the carboxyl group attached to the thiazolidine ring, salt formation occurs with Na+ and K+; these salts are more stable than the parent acid. Sod. PnG is highly water soluble. It is stable in the dry state, but solution deteriorates rapidly at room temperature, though it remains stable at 4°C for 3 days. Therefore, PnG solutions are always prepared freshly. PnG is also thermolabile and acid labile.

Unitage 1 U of crystalline sod. benzyl penicillin = 0.6 μg of the standard preparation. Thus 1 g = 1.6 million units or 1 MU = 0.6 g.

Mechanism Of Action

All βlactam antibiotics interfere with the synthesis of bacterial cell wall. The bacteria synthesize UDP-N-acetylmuramic acid pentapeptide, called ‘Park nucleotide’ (because Park in 1957 found it to accumulate when susceptible Staphylococcus     was grown in the presence of penicillin) and UDP-N-acetyl glucosamine. The peptidoglycan residues are linked together forming long strands and UDP is split off. The final step is cleavage of the terminal D-alanine of the peptide chains by transpeptidases; the energy so released is utilized for establishment of cross linkages between peptide chains of the neighbouring strands (Fig. 51.2). This cross linking provides stability and rigidity to the cell wall.

The βlactam antibiotics inhibit the transpeptidases so that cross linking (which maintains the close knit structure of the cell wall) does not take place. These enzymes and related proteins constitute the penicillin binding proteins (PBPs) which have been located in the bacterial cell membrane. Each organism has several PBPs and PBPs obtained from different species differ in their affinity towards different βlactam antibiotics. This fact probably explains their differing sensitivity to the various βlactam antibiotics.

When susceptible bacteria divide in the presence of a βlactam antibiotic—cell wall deficient (CWD) forms are produced. Because the interior of the bacterium is hyperosmotic, the CWD forms swell and burst → bacterial lysis. This is how βlactam antibiotics exert bactericidal action. Under certain conditions and in case of certain organisms, bizarre shaped or filamentous forms, which are incapable of multiplying, result. Grown in hyperosmotic medium, globular ‘giant’ forms or protoplasts are produced. Lytic effect of these antibiotics may also be due to de-repression of some bacterial autolysins which normally function during cell division.

Rapid cell wall synthesis occurs when the organisms are actively multiplying; βlactam antibiotics are more lethal in this phase.

The peptidoglycan cell wall is unique to bacteria. No such substance is synthesized (particularly, D-alanine is not utilized) by higher animals. This is why penicillin is practically nontoxic to man.

In gram-positive bacteria, the cell wall is almost entirely made of peptidoglycan, which is >50 layers thick and extensively cross linked, so that it may be regarded as a single giant mucopeptide molecule. In gram-negative bacteria, it consists of alternating layers of lipoprotein and peptidoglycan (each layer 1–2 molecule thick with little cross linking). This may be the reason for higher susceptibility of the gram-positive bacteria to PnG.

Blood, pus, and tissue fluids do not interfere with the antibacterial action of βlactam antibiotics.