Download antibiotics penicillins

An antibiotic is ‘a chemical compound derived from or produced by a living organism, which is
capable, in small concentrations, of inhibiting the life processes of micro-organisms.’
Therefore, a substance may be classified as an antibiotic provided it meets the following four
cardinal requirements ; namely :
(a) that it is a product of metabolism
(b) or it is a synthetic product produced as a structural analogue of a naturally occurring
antibiotic.
(c) that it antagonizes the growth and/or the survival of one or more species of microorganisms
(d) that it is effective in low concentrations.
In this section the antibiotics will be discussed explicitly under the following four main heads,
namely :
(a) β-Lactam antibiotics,
(b) Aminoglycoside Antibiotics,
(c) Chloramphenicol, and
(d) Tetracyclines.
Drug Nomenclature
The names given to anti microbials and antibiotics are as varied as their inventor's taste;
however, some helpful unifying convent ions are followed. For example, the penicill ins are
derived from fungi and have names ending in the suffix -cillin, as in ampicillin. The
cephalosporins likewise are fungal products, although their names mostly begin with the prefix
cef - (or , sometimes, following the English practice, ceph-). The synthet ic fluoroquinolones
mostly end in the suf fix -floxacin. Although helpful in many respects, this nomenclature does
result in many related substances possessing quite similar names. This can make remembering
them a burden. Most of the remaining antibiotics are produced by fermentation of soil
microorganisms belonging to various Streptomyces species. By convent ion, these have names
ending in the suf fix -mycin, as in streptomycin. Some prominent antibiotics are produced by
fermentation of various soil microbes known as Mi cromonospora sp. ; these antibiotics have
names ending in -micin, as in gentamicin.
In earlier times, the terms “broad spectrum” and “narrow spectrum” had specific clinical
meaning. The widespread emergence of microbes resistant to single agents and to multiple
agents, however , has made these terms much less meaningful . Nonetheless, it still is valuable
to remember that some antimicrobial families have the potential of inhibiting a wide range of
bacterial genera belonging to both Gram-positive and Gram-negative cultures and so are called
broad spectrum (e.g., the tetracyclines). Others inhibit only a few bacterial genera and are called
narrow spectrum (e.g., the glycopeptides, typified by vancomycin, which are used almost
exclusively for a few Gram-positive and anaerobic microorganisms).
β-LACTAM ANTIBIOTICS
The β-lactam antibiotics may be further sub-divided into two categories, namely :
(a) Penicillins, and (b) Cephalosporins.
The name “ lactam” is given to cyclic amides. In an older nomenclature, the second carbon in an
aliphatic carboxylic acid was designated α, the third β, and so on. Thus, a β- lactam is a cyclic
amide with four atoms in its ring.
Penicillins
Penicillin is the name assigned to the mixture of natural compounds having the molecular
formula C9H11O4N2SR, and differing only in the nature of ‘R’. The penicillin subclass of β-lactam
antibiotics is characterized by the presence of a substituted 5-membered thiazoldine ring fused
to the β-lactam ring.
These are mainly produced by various strains of Penicillium notatum and Penicillium
chrysogenum. There are at least six naturally occurring penicillins, whose chemical names, other
names and the nature of ‘R’ are given in the following table :
Naturally Occuring Penicillins
Preparation of Penicillins
The original fermentation derived penicillins were produced by growth of the fungus Penicillium
chrysogenum on complex solid media, with the result that they were mixtures differing from one
another in the identity of the side-chain moiety.
When a sufficient supply of phenylacetic acid is present in liquid media, this is preferentially
incorporated into the molecule to produce mainly benzylpenicill in (penicillin G in the old
nomenclature). Use of phenoxyacetic acid instead leads to phenoxymethyl penicillin
(penicillin V). More than two dozen different penicillins have been made in this way, but these
two are the only ones that remain in clinical use. The complete exclusion of side chain precursor
acids from the medium produces the fundamental penicillin nucleus, 6-APA, but in poor yield.
By itself, 6-APA has only very weak antibiotic activity, but when substituted on its primary amino
group with a suitable amide side chain, its potency and antibacterial spectrum are profoundly
enhanced.
Clinically Relevant Chemical Instabilities
The most unstable bond in the penicillin molecule is the highly strained and reactive β-lactam
amide bond. This bond cleaves moderately slowly in water unless heated, but it breaks down
much more rapidly in alkaline solutions to produce penicilloic acid, which readily decarboxylates
to produce penilloic acid. Penicilloic acid has a negligible tendency to re-close to the
corresponding penicillin, so this reaction is essentially irreversible under physiologic conditions.
Because the β-lactam ring is an essential portion of the pharmacophore, its hydrolysis
deactivates the antibiotic. A fairly significant degree of hydrolysis also takes place in the liver.
The bacterial enzyme, β-lactamase, catalyzes this reaction as well and is a principal cause of
bacterial resistance in the clinic.
Structure–Activi ty Relationship
The chemical substituents attached to the penicillin nucleus can greatly influence the stability of
the penicillins as well as the spectrum of activity. It is important to recognize whether the
structural changes affect drug stability on the shelf or in the GI tract (in vivo), improve stability
toward bacterial metabolism, or enlarge the spectrum of activity.
The substitution of a side-chain R group on the primary amine with an electron-withdrawing
group decreases the electron density on the side-chain carbonyl and protects these penicillins,
in part , from acid degradation.
This property has clinical implications, because these compounds survive passage through the
stomach better and many can be given orally for systemic purposes. The survival of passage and
degree of absorption under fasting conditions is shown in Table 38.6.
In addition, in vitro degradation reactions of penicillins can be retarded by keeping the pH of
solutions between 6.0 and 6.8 and by refrigerating them. Metal ions, such as mercury, zinc, and
copper, catalyze the degradation of penicillins, so they should be kept from contact with
penicillin solutions. The lids of containers used today are routinely made of inert plastics, in
part, to minimize such problems.
Stability of the penicillins toward β-lactamase is influenced by the bulk in the acyl group
attached to the primary amine. β-Lactamases are much less tolerant to the presence of steric
hindrance near the side-chain amide bond than are the penicillin binding proteins. When the
aromatic ring is attached directly to the side-chain carbonyl and both ortho positions are
substituted by methoxy groups, β-lactamase stability results (Fig. 38.15). Movement of one of
the methoxy groups to the para posit ion, or replacing one of them by a hydrogen, resulted in an
analogue sensitive to β-lactamases. Putting in a methylene between the aromatic ring and 6APA likewise produced a β-lactamase–sensitive agent (see Fig. 38.15). These findings provide
strong support for the hypothesis that its resistance to enzyme degradation is based on
differential steric hindrance. Prime examples of this effect are seen in the drugs methicillin,
nafcillin, oxacillin, cloxicillin, and dicloxicillin.
Spectrum of Penicillins
Drugs of the penicillin group are effective for infections caused by Gram-positive bacteria
(streptococcus, pneumococcus, and others), spirochaetae, and other pathogenic
microorganisms.
Drugs of this group are ineffective with respect to viruses, mycobacteria tuberculosis,
fungi, and the majority of Gram-negative microorganisms.
THE PENICILLIN VARIANTS
The advent of latest developments in ‘medicinal chemistry’, in fact, put forward the following
five penicillin variants, namely :
(a) Natural Penicillins (best streptococcal and narrow spectrum)
(b) Penicillinase-resistant Penicilins (antistaphylococcal)
(c) Aminopenicillins (improved Gram – ve : H-influenzae, Enterococcus, Shigella, Salmonella),
(d) Extended-spectrum (antipseudomonal) penicillins, and
(e) β-Lactamase combinations (expand spectrum to staph, β-lactamase producers).
Effect of side chain on activity
There have been attempts to chemically synthesize penicillins; however, no practical
methods have been found.
An extremely important progress in the development of penicillins took place in 1959,
when the penicillin nucleus, 6-aminopenicillanic acid (6-APA), was removed from the side
chain and isolated from a culture of Penicillium chrysogenum.
Currently, penicillin (benzylpenicillin, penicillin G) is made in huge amounts (tens of
thousands of tons) by the microbiological industry. About two-thirds of the produced penicillin
is used for making 6-APA.
Variations of the acyl regions of the side chain in penicillin molecules produces significant
changes in the properties of resulting compounds. It was discovered that the side chain of the
acyl region of the molecule determines the antimicrobial spectrum, sensitivity
to beta-lactams, and the unique pharmacokinetic features of a specific penicillin. The
unique feature of a few semisynthetic penicillins (meticillin, oxacillin, cloxacillin) is their
efficacy with respect to a culture of microorganisms (staphylococcus) resistant to
benzylpenicillins.
Moreover, some semisynthetic penicillins (ampicillin) are active with
respect to the majority of Gram-negative microorganisms.
Benzylpenicillin (Penicillin G):
is the gold standard penicillin, which is obtained biotechnogically using the fungus P.
chrysogenum as the producer, and phenylacetic acid as the precursor.
Benzylpenicillin or penicillin G has a narrow antimicrobial spectrum. It is active with
respect to Gram-positive bacteria (staphylococcus, streptococcus, and pneumococci),
causative agent of diphtheria, and anthrax bacillus. Gram-negative bacteria are resistant to
it. Benzylpenicillin is broken down by stomach acid and destroyed by staphylococcus
penicillinase.
Benzylpenicillin is the drug of choice for infections caused by sensitive organisms. This
includes streptococci infections (except enterococci), gonococci, and meningococci that
do not produce beta-lactam anaerobes. Benzylpenicillin is used for croupous and focal
pneumonia, skin infections, soft tissue and mucous membranes, periotonitis, cystisis,
syphilis, diphtheria, and other infectious diseases.
Phenoxymethylpenicillin (Penicillin V):
Is also obtained biotechnologically using the fungus P. chrysogenum as the producer and
phenoxyacetic acid as the precursor.
Phenoxymethylpenicillin or penicillin V is acid-resistant and used instead of penicillin G
for oral use. It is active with respect to Gram-positive (staphylococcus, streptococcus,
pneumococcus), and Gram-negative (meningococcus, gonococcus) cocci, spirochaeta,
clostridia, and corynebacteria.
Phenoxymethylpenicillin is used for bronchitis, pneumonia, angina, scarlet fever, gonorrhea,
syphilis, purulent skin and soft-tissue wounds, and other infectious diseases.
Methicillin:
Like other semisynthetic penicillins, methicillin exhibits an antibacterial effect similar to that
of benzylpenicillin. The main difference between methicillin and benzylpenicillin is that it is
not inactivated by the enzyme penicillinase, and therefore it is effective with respect to agents
producing this enzyme (staphylococci). It is used for infections caused by benzylpenicillin
resistant staphylococci (septicemia, pneumonia, empyemia, osteomyelitis, abscesses, infected
wounds, and others).
synthesized by acylating 6APA with 2,6-dimethoxybenzoic acid chloride
in the presence of triethylamine
Oxacillin:
is synthesized by reacting 5-methyl-3-phenyl-4-isoxazolcarboxylic acid chloride (32.1.1.9) with
6-APA in the presence of sodium bicarbonate. The 5-methyl-3-phenyl-4-isoxazolcarboxylic
acid chloride (32.1.1.9) is synthesized by the following scheme.
Reacting benzaldehyde with hydroxylamine gives benzaldoxime (32.1.1.5), which
when oxidized by chlorine gives benzhydroxamic acid chloride (32.1.1.6). This is reacted
with acetoacetic ester in the presence of sodium ethoxide, giving the ethyl ester of
5-methyl-3-phenyl-4-isoxazolcarboxylic acid (32.1.1.7). Alkaline hydrolysis of the resulting
ester gives the corresponding acid (32.1.1.8), which is reacted with thionyl chloride to
give the acid chloride necessary for acylation.
In terms of the spectrum of antimicrobial action, oxacillin is analogous to benzylpenicillin.
However, it combines the resistance to penicillinase with durability in an acidic medium, which
allows it to be used not only intramuscularly, but also orally.
Ampicillin:Ampicillin has a broad spectrum of action and is effective for infections caused by
various sensitive organisms; it is active with respect to Gram-positive and Gram-negative cocci,
intestinal bacilli, salmonella, shigella, enterococci, listeria, and a few strains of hemophilic
bacilli. Ampicillin is the drug of choice for infections caused by beta-lactamase negative
types of Haemophilus influenzae, Listeria monocytogenes, and enterococci. It is used for
bronchitis, pneumonia, dysentery, salmonella, whooping cough, pyelonephritis, endocarditis,
sepsis, and so on.
directly acylating 6-APA with phenylglycine
chloride hydrochloride
Amoxycillin:Amoxycillin, like ampicillin, has a broad spectrum of use.
Indications for use are the same as with ampicillin.
direct reaction of D-(-)-2-(4-hydroxyphenyl)glycine chloride
hydrochloride with trimethylsylil ester of 6-APA
Carbenicillin:
is synthesized by direct acylation of 6-APA in the presence of sodium bicarbonate by
phenylmalonic acid monobenzyl ester chloride, which forms the benzyl ester of carbenicillin
(32.1.1.31), the hydrogenolysis of which using palladium on carbon or calcium carbonate
as catalyst gives the desired product
Carbenicillin has a broad spectrum of antibacterial use with respect to Gram-negative and
Gram-positive microorganisms. It is mzinly used for diseases such as urinary tract infections,
septicemia, endocarditis, meningitis, osteomelitis, peritonitis, purulent otitis, infected
wounds, infected burns, and so on that are caused by Gram-negative microorganisms which
are sensitive to such antibiotics.