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The term antibiotic is originated from the word antibiosis [against life]. They are compounds obtained from various species of microorganisms such as bacteria, fungi, actinomycetes. They can suppress the growth of other microorganisms and eventually may destroy them. The difference amongst them may be physical, chemical, pharmacological properties, antibacterial spectra, the mechanism or mode of action. They have made it possible to cure the diseases caused by pneumonia, tuberculosis and meningitis and save the lives of millions of people around the world.
MODIFIED PEPTIDES: PENICILLINS, CEPHALOSPORINS, EXAMPLES OF -LACTAM ANTIBIOTICS Penicillins The penicillins are the oldest of the clinical antibiotics, but are still the most widely used. The first of the many penicillins to be employed on a significant scale was penicillin G (benzylpenicillin), obtained from the fungus Penicillium chrysogenum by fermentation in a medium containing corn-steep liquor. Penicillins contain a fused -lactam-thiazolidine structure, which has its biosynthetic origins in a tripeptide, the components of which are l-aminoadipic acid (formed in -lactam-producing organisms from lysine via piperideine-6-carboxylic acid), l-cysteine and l-valine.
Other -Lactams The fused -lactam skeletons found in penicillins and cephalosporins are termed penam and cephem respectively variants containing the basic -lactam ring system are also found in nature. Although these are derived from amino acid precursors, in contrast to the penicillins and cephalosporins, they are not usually the products of NRPS enzymes. Of particular importance is the clavam or oxapenam fused-ring system typified by clavulanic acid from Streptomyces clavuligerus.
Clavulanic acid is usually combined with a standard penicillin, e.g. with amoxicillin (as coamoxyclav) or with ticarcillin, to act as a suicide substrate and provide these agents with protection against class A -lactamases, thus extending their effectiveness against a wider range of organisms.
The naturally occurring monobactams show relatively poor antibacterial activity, but alteration of the side-chain, as with penicillins and cephalosporins, has produced many potent new compounds. Unlike those structures, the non-fused -lactam ring is readily accessible by synthesis, so all analogues are produced synthetically. The first of these to be used clinically is aztreonam.
Tetracycline, a valuable antibiotic is a polyketide which is produced on a large scale from Streptomyces aureofaciens
Vancomycin, a glycopeptide antibiotic produced in cultures of Amycolatopsis orientalis (formerly Streptomyces orientalis) and has activity against Gram-positive bacteria, especially resistant strains of staphylococci, streptococci, and enterococci. Vancomycin is not absorbed orally, so must be administered by intravenous injection. The antibiotic may cause toxicity to ear and kidneys.
The penicillins are complex mixtures of closely related compounds isolated from the beers resulting from fermentation of the molds, Penicillium notatum and Penicillium chrysogenum. The active compounds proved to be amides of 6-aminopenicillanic acid ( 6-APA) (1) with differing acyl groups attached to the amine of the -lactam ring. 6-APA possesses weak but definite antibacterial properties, and its structure represents the minimum structural requirements for the characteristic bioactivity of the penicillins.
The incorporation of an acyl side chain (2), particularly one containing an aryl residue, increases potency by 50 to 200-fold.
Thus 6-APA (1) is the penicillin pharmacophore, and the amide function serves to modulate the kind and intensity of antimicrobial activity. All the clinically useful analogs that have reached the marketplace have flowed from this basic fact or have resulted from the adventitious discovery of analogous substances from natural sources.
At higher pH values, benzylpenicillin suffers simple -lactam ring opening and gives penicilloic acid . The strained -lactam (cyclic amide) ring is more susceptible to hydrolysis than the unstrained side-chain amide function, since the normal stabilizing effect of the lone pair from the adjacent nitrogen is not possible due to the geometric restrictions .
Supplementation of the fermentation medium with acids other than phenylacetic acid was used to provide structurally modified penicillins, though the scope was limited to a series of monosubstituted acetic acids by the specificity of the fungal enzymes involved in activation of the acids to their coenzyme A esters. The most important new penicillin produced was phenoxymethylpenicillin (penicillin V), a result of adding phenoxyacetic acid to the culture (Figure 7.40). This new penicillin had the great advantage of being acid resistant, since the introduction of an electron-withdrawing heteroatom into the side-chain inhibits participation of the side-chain carbonyl in the reaction shown in Figure 7.38. Thus, penicillin V is suitable for oral administration, and still has particular value for respiratory tract infections and tonsillitis.
Penicillin, destroys bacteria by inhibiting the enzyme that synthesizes bacterial cell walls
Bacteria develop resistance to penicillin by secreting penicillinase, an enzyme that destroys penicillin by hydrolyzing its -lactam ring before the drug can interfere with bacterial cell wall synthesis.
Bacteria that are resistant to penicillin secrete penicillinase, an enzyme that catalyzes the hydrolysis of the b-lactam ring of penicillin. The ring-opened product has no antibacterial activity.
(3) semisynthetic production (in which 6-aminopenicillanic acid obtained by a process involving fermentation, and suitably activated acids are subsequently reacted chemically to form penicillins with new side chains)
(4) total synthesis (potentially the most powerful method for making deep-seated structural modifications but which is at present unable to compete economically with the other methods).
Penicillin V is a semisynthetic penicillin that is in clinical use. It is not a naturally occurring penicillin; nor is it a true synthetic penicillin because chemists dont synthesize it. The Penicillium mold synthesizes it after the mold is fed 2-phenoxyethanol, the compound it needs for the side chain.
Feeding of phenylacetic acid in the fermentation led to a simplification of the mixture of penicillins produced by the fungus due to preferential uptake of this acid and its incorporation into benzylpenicillin, Inclusion of the appropriate acids in the culture medium thus afforded, respectively, phenoxymethylpenicillin ( penicillin V), phenethicillin , propicillin and phenbencillin.
The most important new penicillin produced was phenoxymethylpenicillin (penicillin V), a result of adding phenoxyacetic acid to the culture These modifications served to increase stability of the lactam bond towards hydrolysis and thus conferred some degree of oral activity. The nature of the penicillin derivatives accessible by this "feeding" route was severely limited by the fact that the acylating enzyme of the Penicillium molds would accept only those carboxylic acids which bore at least some resemblance to its natural substrates. A breakthrough in this field was achieved by the finding that rigid exclusion of all possible side-chain substrate! from the culture medium afforded 6APA as the main fermentation product.
Supplementation of the fermentation medium with acids other than phenylacetic acid was used to provide structurally modified penicillins, though the scope was limited to a series of monosubstituted acetic acids by the specificity of the fungal enzymes involved in activation of the acids to their coenzyme A esters. The most important new penicillin produced was phenoxymethylpenicillin (penicillin V), a result of adding phenoxyacetic acid to the culture (Figure 7.40). This new penicillin had the great advantage of being acid resistant, since the introduction of an electron-withdrawing heteroatom into the side-chain inhibits participation of the side-chain carbonyl in the reaction shown in Figure 7.38. Thus, penicillin V is suitable for oral administration, and still has particular value for respiratory tract infections and tonsillitis.
Structure of Penilloaldehyde All penicillins on vigorous hydrolysis gave substituted acetic acid and aminoacetaldehyde
Synthesis of penilloaldehyde
Hydrolysis of Penicillins yielded D-penicillamine, penilloaldehyde and CO2 . At this point it was explained that the formation of CO2 is from an unstable - keto acid named penaldic acid.
-CO2
Penilloic acid
Penicillamine + Penilloaldehyde
H2O/HgCl2