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Penicillins And Cephalosporins |
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Penicillins And Cephalosporins - Penicillin was the first antibiotic discovered. Because of its high potency against gram positive organisms and its normally low toxicity, it is widely used in the treatment of bacterial infections the original penicillins were mixtures of compounds having different side chains. Addition of phenyl acetic acid to the fermentation mixtures results in the synthesis of a single, compound called penicillin G or benzyl penicillin. Penicillin G has limited effectiveness when given orally, because it is readily inactivated at low pH in the stomach.
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Penicillin V or phenoxymethyl penicillin was obtained by replacing phenyl acetic acid by phenoxyacetic acid. It. is mote reliable than penicillin when given by mouth.
Penicillins and cephalosporins are both β-lactam antibiotics having 6-aminopenicillanlc acid (6-APA) and 7.aminopenicillanlc acid (7-APA) nuclei, respectively. The penicillin molecule consists of a 4-membered β-lactam ring to which is attached a side group, and a 5-membered saturated heterocyclic ring. Cephalosporins have a 6-membered unsaturated heterocyclic ring. The β-lactam ring, especially the bond between N and CO, reacts with enzymes involved in the synthesis of the bacterial cell wall and produces the inhibitory effect.
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The effectiveness of the B-lactam antibiotics has been greatly increased by side- chain modifications. Treatment of penicillin G with bacterial enzymes removes the benzyl side chain, leaving 6-aminopeniciUaoic acid (6-APA). Moulds grown in a medium lacking any acyl side chain donor also produce 6-AP A. Condensation of this inactive precursor with any carboxylic acid can form several different types of penicillins. Some of these semi synthetic penicillins are listed.
It is also possible by chemical methods to transform the penicillin nucleus into cephalosporin by conversion, of the 4:5 to the 4:6 ring systems.
The improvements achieved by producing semi synthetic penicillins include, (i) increased stability to acids, (ii) greater usefulness against resistant strains and (iii) increased activity against gram negative bacteria.
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Many staphylococci and certain other species develop resistance to penicillin G.This is due to the fact that they produce the enzyme penicillinase (β-lactamase) which hydrolyses the lactam bond and converts penicillin to penicilloic acid (which lacks antibacterial activity). Some semi synthetic penicillins, e.g. methicillin and cloxacillin, are not affected by lactamase, and are therefore useful against resistant strains. Other derivatives like oxacillin and nafcillin have increased stability to acids, and can hence be given orally.
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The greatest advantage of the modified penicillins is the broadening of the antimicrobial spectrum. The original penicillins are active only against gram positive bacteria, neisseriae and treponemes. Modified penicillins like ampicillin (α-aminobenzyl) and carbenicillin are also active against many gram negative bacteria.
The amino group on the side chain of ampicillin gives it the positive charge which increases penetration through the negatively charged lipopoly saccharide layer of the bacterial cell envelope. Increased activity against gram negative bacteria is, however, accompanied by reduced activity against gram positive bacteria. The activity of ampicillin against gram positive organism is half that of penicillin G. Carbenicillin is used mainly against Pseudomonas.
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Cephalosporin
Cephalosporin C was isolated from the mould Cephalosporium, and has low potency. Its 7-APA nucleus can, however, be used as the base for producing semi synthetic derivatives like cephalothin, cefoxitin and cephaloridine. One advantage of cephalosporins over penicillins is that they do not cause allergic reactions. Hence they are used as alternatives to penicillins in patients who are allergic to the latter.
Antibodies with penicillin-like action on cell wan biosynthesis, through at other stages, include bacitracin, vancomycin and cycloserine. They, however, have restricted chemotherapeputic use because of their higher toxicity.
Bacitracin
Bacitracin is a polypeptide antibiotic which is said to inhibit cell wall synthesis during the formation of the linear polymer by a specific inhibitory action on pyroph sphatase it also disorganizes the ce1l membrane. It is not used systemically because of its toxicity. It is, however, sometimes used locally against gram-positive bacteria, e.g. in colon surgery.
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