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PENICILLIN ANTIBIOTICS
INTRODUCTION:
In 1929, Alexander Fleming isolated penicillin from a strain of Penicillium notatum.
By 1941, World War II, benzylpenicillin was used to treat patients with streptococcal, gonococcal,
and treponemal infections.
Penicillin-G natural penicillin is still the drug of choice for many types of infections (throat
infections, meningitis, syphilis, and certain types of endocarditis).
Penicillins are a group of antibiotics originally obtained from Penicillium moulds, principally P.
chrysogenum and P. rubens.
The penicillins are the most commonly used antibiotics in pediatrics and can be divided broadly into
four different groups: (1) natural penicillins, (2) penicillinase-stable penicillins, (3) aminopenicillins,
and (4) extended-spectrum penicillins.
Most penicillins in clinical use are synthesized by P. chrysogenum using deep tank fermentation and
then purified.
The chief side effects of penicillin are hypersensitivity reactions, including skin rash, hives, swelling,
anaphylaxis, or allergic shock. The more serious reactions are uncommon
Antibiotics in the penicillin class are one of the most commonly prescribed antibiotics and include
many individual medications, such as penicillin G, amoxicillin, nafcillin, oxacillin, dicloxacillin,
flucloxacillin, ampicillin, carbenicillin, ticarcillin, and piperacillin.
Mechanism of Action of Penicillins
Penicillins are bactericidal they inhibit the cell wall of bacteria by blocking transpeptidase after
binding to penicillin-binding protein (PBP), and prevent its synthesis.
Bacteria cells die because of cell lysis.
Penicillins don’t kill other cells in the body.
Chemistry and Structure-Activity Relationships of Penicillins
Nomenclature of penicillins is done in different ways
The Nitrogen atom is assigned number 1st and Sulfur is assigned number 4th position. So, chemically
it is 6-Acetylamino-2,2-dimethyl-7-oxo-1-thia-4-aza-bicyclo[3.2.0]heptane-3-carboxylic acid (USP).
The Sulfur atom is assigned number 1st, and Nitrogen is assigned number 4th position, So, chemically
it is 6-Acetylamino-3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid
(Chemical abstract).
The basic chemical structure of all penicillins consists of a beta-lactam ring, a thiazolidine ring, and
a side chain (acylamino or 6-aminopenicillanic acid).
Manipulations of the side chain have produced compounds that are stable against certain bacteria,
such as Staphylococcus aureus, which produce beta-lactamase enzymes (penicillinase).
The side chain sterically inhibits the beta-lactamase hydrolysis of the beta-lactam ring and making
more stable for gastric acid breakdown.
The side chain varies with each penicillin compound and generally determines the spectrum of
activity, as well as the pharmacokinetic properties of the compound.
The bicyclic ring system, at the 1st position “S”, at the 2nd position 1-alpha, and 1-beta alkyl groups,
at the 3rd position “-COOH” group, at 4th position “N’’, at the 5th and 6th positions, the cis-orientation
of alpha “H” the trans “N” and at 7th position “ ketone” group are essential for antibacterial activity.
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Penicillin derivatives
O
•H2C
O
•HC
R=Benzyl=(Benzyl penicillin)
•H2C
R=2,5-dimethoxy phenyl= (Methicillin)
Cl
O
R=Phenoxy methyl=(PenicillinV)
C
•
R=3-(2-chlorophenyl)-5-methyl-4-isoxazolyl= (Cloxacillin)
•HC
NH2
R=Amino benzyl=(Ampicillin)
•HC
OH
NH2
R=Amino-p-hydoxy benzyl=(Amoxicillin)
H
N
N
HN
N
O
N
N
O
O O
H
N
CH
R= 4-Ethyl-2,3-dioxo-piperazine1-carboxylic acid benzylamide= (Pipracillin)
CH
O
O
R=Ureido (Ureiod penicillin)
H
O
S
H
O
O
OH
N
N
O
O
COOH
Clavulanic aacid or
Sulbactam or
3-(2-Hydroxy-ethylidene)-7-oxo-4-oxa-13,3-Dimethyl-4,4,7-trioxo-4-thiaaza-bicyclo[3.2.0]heptane-2-carboxylic acid
1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid
COOH
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Classification of Penicillins
 Natural Penicillins
 Penicillin G is a natural penicillin that is produced directly from the fermentation of Penicillium
crysogenum.
 The natural penicillins (G and V) have activity against non-beta-lactamase producing gram-positive
cocci, (Viridans streptococci, group A streptococci, Streptococcus pneumonia), and anaerobic
streptococcus (non-penicillinase-producing strains of Staphylococcus aureus and coagulasenegative Staphylococcus).
 Natural penicillins are inactive against beta-lactamase-producing organisms.
Penicillinase-Resistant Penicillins
 The agents in this group are also known as the “antistaphylococcal penicillins”. The addition of an
isoxazolyl side chain to the penicillin compound protects the beta-lactam ring from acid hydrolysis
by penicillinases produced by Staphylococcus sp.
 Methicillin, the first agent synthesized in this group, is rarely used currently due to a higher incidence
of occurrence of interstitial nephritis and is no longer commercially available in the United States.
 Nafcillin, and oxacillin are the agents commonly used parenterally, while dicloxacillin is available for
oral use.
 These agents have activity against Staphylococcus sp. (including penicillinase-producing strains).
 Strains of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant
Staphylococcus epidermidis (MRSE) exist and can be the prevalent Staphylococcal organism in
hospital wards within the hospital. These organisms are not sensitive to penicillinase-resistant
penicillins.
Aminopenicillins
 The enhanced spectrum of these drugs includes activity against gram-negative bacilli (H. influenzae,
E. coli, Proteus mirabilis, Salmonella sp., and Shigella sp).
 Presently, many strains of these gram-negative organisms are resistant to ampicillin.
 Combinations of an aminopenicillin plus a beta-lactamase inhibitor (clavulanic acid or sulbactam),
are useful for the treatment of infections caused by beta-lactamase-producing organisms.
Carboxypenicillins
 A carboxyl group substitution in place of the amino group yields penicillin compounds that have a
greater gram-negative spectrum of action, including activity against Pseudomonas aeruginosa, most
likely due to increased bacterial penetration through the cell wall.
 Carbenicillin and ticarcillin are the two drugs in this class.
 Coverage against Klebsiella and Serratia are less predictable and, unlike ampicillin, these
compounds have little activity against Enterococcus. These agents are not effective against betalactamase producing organisms unless combined with a beta-lactamase inhibitor (e.g. ticarcillin plus
clavulanic acid).
Ureidopenicillins and Piperazine Penicillin
 In order to increase gram-negative coverage and particularly coverage against Pseudomonas
aeruginosa, a ureido group addition to the penicillin structure produces the compounds azlocillin
and mezlocillin.
 A ureido group plus a piperazine side chain produces piperacillin.
 The gram-negative coverage of this class of penicillins includes that of the carboxypenicillins, plus
coverage against Klebsiella, Serratia, Enterobacter, Enterococcus, and increased anaerobic coverage.
 As with the carboxypenicillins, drugs in this class are susceptible to inactivation by bacterial betalactamase production, unless combined with a beta-lactamase inhibitor (e.g. piperacillin plus
tazobactam).
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Therapeutic uses of Penicillins
Antibiotics will not work for colds, flu, or other viral infections.
Reasons
Why Penicillin-V being synthetic penicillin is considered Natural penicillin?
Reply: Penicillin V is a derivative of penicillin G and because of similarities in the spectrum of activity,
is considered natural penicillin.
Why natural penicillins should not be used for the treatment of gonorrhea?
Reply: Similar to staphylococcal infection, natural penicillins should not be used for the treatment of
Gonorrhea due to the increased potential of a resistant organism and subsequent treatment failure.
Why is methicillin no longer used?
Reply: Methicillin was the first semisynthetic penicillinase-resistant penicillin. It has been withdrawn
from the market in the United States because of the high incidence of interstitial nephritis associated
with its use.
What are Clavulanic acid and sulbactam antibiotics?
Reply: Clavulanic acid, and sulbactam are in a class of medications called beta-lactamase inhibitors.
Both work by preventing bacteria from destroying amoxicillin.
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