Penicillin action

The biochemical basis of penicillin action continues to be an area of active investigation. Penicillins are highly specific inhibitors of enzyme(s) involved in the synthesis of the bacterial cell wall, a structure not present in mammalian cells. Three principal factors are thought to be important for effective antibacterial action by a penicillin ... 

Figure 7.10 Bacterial cell wall synthesis. 1) Alanine molecules are added to a carbohydrate tripeptide to form a "T" shaped cell wall precursor. This reaction is inhibited by D-cycloserine. 2) The precursor is transported across the plasma membrane by a carrier. Vancomycin inhibits the transport process. 3) The transporter is recycled to the inside of the cell to carry other precursors. Bacitracin inhibits this step. 4) The precursor is linked to the existing cell wall structure by transpeptidase. Penicillins, cephalosporins, imipenem and aztreonam inhibit the transpeptidase. Transpeptidase is one of several penicillin binding proteins and is not the only site of penicillin action.

Following Tipper s and Strominger s suggestions, there followed an intensive period of activity to purify and identify the targets for penicillin action. 

Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important P-lactamases (10—14,57,58) including penases, and Richmond-Sykes types 11, 111, IV, V, VI ([Bacteroides). Type I Cephases are poorly inhibited. Clavulanic acid synergizes the activity of many penicillins and cephalosporins against resistant strains. The chemistry (59—63), microbiology (64,65), stmcture activity relationships (10,13,60—62,66), biosynthesis (67—69), and mechanism of action (6,26,27,67) have been reviewed. 

Cephalosporin 5-oxides and penicillin 5-oxides (221) can be converted into isothiazol-3-ones (222) by the action of bases. These reactions proceed via an intermediate azetidinonesulfenic acid (223 Scheme 37) (77SST(4)339). Attempts to prepare /3-lactam compounds from isothiazoles have, as yet, been unsuccessful (81X2181). 

Ampicillin—see Penicillin, D-n-aminobenzyl-Amprolium coccidiostat mode of action, 1, 212 as veterinary product, 2, 515 Amquinsin, 2, 517 Amylobarbitone metabolism, 1, 237 Anabasine, 2, 511 synthesis, 2, 385 Anabasine, N-methyl-N -oxide... 

In subsequent studies,22 Sheehan et al. demonstrated that the action of diisopropylcarbodiimide on penicilloate 24, prepared by protection of the free primary amino group in 23 with trityl chloride (see Scheme 6b), results in the formation of the desired -lactam 25 in a very respectable yield of 67 %. In this most successful transformation, the competing azlactonization reaction is prevented by the use of a trityl group (Ph3C) to protect the C-6 amino function. Hydrogenolysis of the benzyl ester function in 25, followed by removal of the trityl protecting group with dilute aqueous HC1, furnishes 6-aminopenicillanic acid (26), a versatile intermediate for the synthesis of natural and unnatural penicillins. 

Penicillin has an interesting mode of action it prevents the cross-linking of small peptide chains in peptidoglycan, the main cell wall polymer of bacteria. Pre-existing cells are unaffected, but all newly produced cells are abnormally grown. The newborn cells are unable to maintain their wall rigidity, and they are susceptible to osmotic lysis. 

The clinical aspects of several antibiotics such as penicillin G, cephalosporin and many other antibiotics are summarised in Table 11.1. The potential microorganisms for the production of various antibiotics and then activities on site or mode of action of the antibiotics are also listed. 

Identify the uses, general drug actions, and general adverse reactions, contraindications, precautions, and interactions of the penicillins. 

Discuss ways to promote optimal response to therapy, nursing actions to minimize adverse effects, and important points to keep in mind when educating patients about the use of penicillin. 

The penicillins have the same type of action against bacteria. Fbnicillins prevent bacteria from using a substance that is necessary for the maintenance of the bacteria s outer cell wall. Unable to use this substance for cell wall maintenance, the bacteria swell, rupture, assume unusual shapes, and finally die (Pig. 7-1). 

Cephalosporins affect the bacterial cell wall, making it defective and unstable This action is similar to the action of penicillin. The cephalosporins are usually bactericidal (capable of destroying bacteria). 

Studies on the mode of action of the penicillins in inhibiting bacterial cell-wall biosynthesis suggest that the members of this class of antibiotics (including the closely related cephalosporins) are conformationally restricted substrate analogs... 

Bacterial resistance to antibiotics has been recognized since the first drugs were introduced for clinical use. The sulphonamides were introduced in 1935 and approximately 10 years later 20% of clinical isolates of Neisseria gonorrhoeae had become resistant. Similar increases in sulphonamide resistance were found in streptococci, coliforms and other bacteria. Penicillin was first used in 1941, when less than 1 % of Staphylococcus aureus strains were resistant to its action. By 1947,3 8% of hospital strains had acquired resistance and currently over 90% of Staph, aureus isolates are resistant to penicillin. Increasing resistance to antibiotics is a consequence of selective pressure, but the actual incidence of resistance varies between different bacterial species. For example, ampicillin resistance inEscherichia coli, presumably under similar selective pressure as Staph, aureus with penicillin, has remained at a level of 30-40% for mai years with a slow rate of increase. Streptococcus pyogenes, another major pathogen, has remained susceptible to penicillin since its introduction, with no reports of resistance in the scientific literature. Equally, it is well recognized that certain bacteria are unaffected by specific antibiotics. In other words, these bacteria have always been antibiotic-resistant. 

Figure 2.14 Relation between the EEG recorded from an epileptic focus on the surface of the cerebral cortex (EEG) and the activity of a single cortical neuron recorded extracellularly (e.c.) and intracellularly (i.c.) during an experimental epilepsy induced by topical application of penicillin. Note that the large EEG excursions correspond to the large (synchronised) depolarisations of the neuron, not to action potential discharges. (Adapted from Brain Res. 52 Ayala, GF et al. Genesis of Epileptic Interictal Spikes. New Knowledge of Cortical Feedback systems suggests a Neurophysiological Explanation of Brief Paroxysms, 1-17 (1973) with permission from Elsevier Science)...

Mode of action Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins, which in turn inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls bacteria usually lyse from ongoing autolytic enzyme activity... 

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