Penicillins by Dr M H Ghante.pdf

of 18
β-LACTAM ANTIBIOTICS
A. PENICILLINS
1. Benzyl penicillins
a. Penicillin G
i. benzylpenicillin sodium,
ii. Procaine benzylpenicillin,
iii. Benzathine penicillin
2. Phenoxy-penicillins (oral penicillins)
a. Penicillin V
b. Propicillin
3. Penicillinase resistant penicillins (anti-staphylococcal penicillins)
a. Oxacillin
b. Dicloxacillin
c. Flucloxacillin
4. Aminobenzyl penicillins
a. Ampicillin
b. Amoxicillin
5. Ureidopenicillins (broad-spectrum penicillins)
a. Mezlocillin
b. Piperacillin
6. ß-Lactam/ ß-lactamase inhibitors
a. sulbactam & Ampicillin
b. Clavulanate & Amoxicillin
c. Tazobactam & Piperacillin
d. Sulbactam in free combinations
B. Cephalopsorins

of 18
β- Lactam Antibiotics- Penicillin(s)
1. Chemistry and nomenclature:
 A β- lactam is a cyclic amide with four atoms in its ring.
 As the name “lactam” indicates cyclic amide which is generally considered as
analogous to the name “lactone” which is indicated for cyclic esters.
 In an older nomenclature, α was designated to the second carbon in an
aliphatic carboxylic acid/ or a carbon bears functional group such as
carboxyllic acids, and β to the third, and so on- as shown in above structure.
 The contemporary name for this ring system is azetidinone.
 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.
Nomenclature:
Two different numbering approaches are used for the fused bicyclic heterocyclic
system of penicllin of beta lactam class.
1. The Chemical Abstracts system initiates the numbering with the sulfur atom
and assigns the ring nitrogen the 4-position. Thus, penicillins are named as
4-thia-l-azabicyclo[3.2.0]heptanes,

of 18
2. The numbering system adopted by the USP is the reverse of the Chemical
Abstracts procedure, assigning number 1 to the nitrogen atom and number 4
to the sulphur atom.
 Three simplified forms of penicillin nomenclature have been adopted for
general use.
o The first uses the name “penam” for the unsubstituted bicyclic system,
including the amide carbonyl group,
o Thus, penicillins according to the Chemical Abstracts system as 5-
acylamino-2,2-dimethylpenam-3-carboxylic acids.
o The second, more frequently, uses the name “penicillanic acid” is 2, 2-
dimethyl and 3-carboxyl.
3. A
third form, uses trivial nomenclature to name the entire 6-
carbonylaminopenicillanic acid (6-APA) portion of the molecule penicillin and
then distinguishes compounds on the basis of the R group of the acyl portion
of the molecule.
Example:

of 18
o penicillin G - benzylpenicillin,
o penicillin V - phenoxymethylpenicillin,
o methicillin is 2,6-dimethoxyphenylpenicillin, and so on.
1.1 Sterochemistry of penicillin
 The penicillin molecule contains three chiral carbon atoms (C-3, C-5, & C-6).
 PC’s are the cis relationship between
o the two hydrogens at positions 5 and 6, a
o free 3-carboxylate and a 6-amide.
 The carbon atom bearing the
o acylamino group (C-6) has the L configuration,
o Whereas the carbon to which the carboxyl group is attached has the D
configuration.
o Thus, the acylamino and carboxyl groups are trans to each other, with
the former in the α and the latter in the β orientation relative to the
penam ring system.
 The absolute stereochemistry of the penicillins is designated 3S:5R:6R, as
shown below/ above

of 18
 The atoms composing the 6-aminopenicillanic acid (6-APA) portion of the
structure are derived biosynthetically from two amino acids,
o L-cysteine (S-1, C-5, C-6, C-7, and 6-amino) and
o L-valine (2,2-dimethyl, C-2, C-3, N-4, and 3-carboxyl).
Amino acid components of 6-
aminopenicillanic acid (6-APA)
structure
2. Classification (according to source/ synthesis way)
There are several ways to classify penicillin antibiotic of beta lactam class. Few are
enlisted below
Natural penicillins Semi-synthetic penicillins
– Extracted from the cultural
solution of penicillia.
– Prototype is penicillin G
– Is pH sensitive. Therefore
not given orally.
– Effective against G+ve
– Susceptible to penicillinase
– Produce by growing Penicillium in culture
so that only the nucleus is synthesized.
– Attach R group in lab. OR
– Grow Penicillium, extract replace R by/
with required R group.
– Have broader spectrum.
– Effective against G-ve cells, too.
– Are not resistant to penicillinases
Classification according to SAR
Class Example
Aminopenicillins Ampicillin, Amoxicillin
Acid-stable Penicillin V
Penicillinase-resistant oxacillin
Extended/ broad -spectrum Ampicillin, Amoxicillin
Antistaphylococcal nafcillin, Oxacillin, Dicloxacillin
Anti-Pseudomonal [Carboxy] Ticarcillin, [Ureido] Piperacillin,
carbenicillin,
Beta-lactamase inhibitors clavulanic acid, sulbactam, tazobactam

of 18
o Resistance to penicillin
 decreased permeability to penicillins
 Alteration of the number or nature of porins in the cell
envelope
 Changes in the affinity of PBPs for penicillins/ Altered PBP
binding due to mutation
 Degradation of antibiotics/ Penicllins by Beta lactamase

of 18
3. Structure–Activity Relationship
The chemical substituent’s attached to the penicillin nucleus can greatly influence
the
 the spectrum of activity/broadened spectrum
 stability of the penicillin in terms of
o in gastric juice &
o drug stability on the shelf or in the GI tract (in vivo),
o against bacterial resistance- improve stability toward bacterial
metabolism (beta lactamase),
 Chemical Degradation
 Bacterial Resistance
 Penicillinase-Resistant Penicillins
 Extended-Spectrum Penicillins
 Protein Binding
 Allergy to Penicillins
Common SAR requirements/ requisites
• The strained (β-lactam ring is essential)
• The free carboxylic acid is essential
• The bicyclic system is important
– confers strain on the β-lactam ring—the greater the strain, the greater
the activity,
– but the greater the instability of the molecule to other factors.
• The acylamino side-chain is essential
• The stereochemistry of the bicyclic ring with respect to the acylamino side-
chain is important.
3.1 SAR for acid stable PC
– Acid-catalyzed degradation in the stomach contributes strongly to the poor
oral absorption of penicillin.
– Thus, efforts to obtain penicillins with improved pharmacokinetic and
microbiological properties have focused on acyl functionalities that would

of 18
minimize sensitivity of the β-lactam ring to acid hydrolysis while
maintaining antibacterial activity.
– Substitution of an electron-withdrawing group in/at the α-position of
benzylpenicillin markedly stabilizes the penicillin to acid-catalyzed hydrolysis.
– Thus,
o phenoxymethylpenicillin-PC-V,
o α -aminobenzylpenicillin-ampicillin, &
o α-halobenzylpenicillin
are significantly more stable than benzylpenicillin in acid solutions.
– As α-aminobenzylpenicillin (ampicillin) exists as the protonated form in acidic
(as well as neutral) solutions, and the ammonium group is known to be
powerfully electron-withdrawing.
Comparative Acid resistance to penicillin’s
Poor Fair Good
PC-G, Methicillin,
carbenicillin, ticarcilllin,
piperacillin, mezlocillin
Nafcillin
PC-V, oxa, clox, dicloxacilllin,
ampi & amoxy
3.2 Bacterial Resistance
3.2.a-Bacterial enzymes responsible for resistance
– Enzymes penicillinases is the nonspecific name, is of two general types:
o β-lactamases &
o acylases.
– By far, the more important of these are the β-lactamases, enzymes that
catalyze the hydrolytic opening of the β-lactam ring of penicillins to produce
inactive penicilloic acids.
Penicillin resistant bacteria possess β-lactamase enzymes which
deactivate the drug by opening the β-lactam ring

of 18
– Some bacteria, in particular most species of G-ve bacilli, are naturally
resistant to the action of penicillins.
– The well-known resistance among strains of Staphylococcus aureus is due to
β-lactamase production.
– Specific acylases (enzymes that can hydrolyze the acylamino side chain of
penicillins) have been obtained from several species of G-ve bacteria,
however their probable involvement in resistance is yet to be revealed.
– Another important resistance mechanism, especially in G-ve bacteria, is
decreased permeability to penicillins which might be contributed by one of
the followings
o Alteration of the number or nature of porins in the cell envelope
o Changes in the affinity of PBPs for penicillins.
o Altered PBP binding has been demonstrated in non–β-lactamase-
producing strains of penicillin-resistant Neisseria gonorrhoeae and
methicillin-resistant S. aureus (MRSA).
3.2.b-Penicilinase-Resistant Penicillins
 In general, increasing the steric hindrance at the α-carbon of the acyl group
increased resistance to staphylococcal β-lactamase, with maximal resistance
being observed with quaternary substitution.
(↑ Steric hindrance↑ resistance beta-lactamase—max with 4°/ quaternary
substitution)
o More productive in terms of antibacterial potency, was the observation
that the α-acyl carbon could be part
o of an aromatic (e.g.,phenyl or naphthyl) or
o heteroaromatic (e.g., 4-isoxazoyl)
o Substitutions at the ortho positions of a phenyl ring
– e.g., 2,6-dimethoxy [methicillin]) or
– the 2-position of a 1-naphthyl system (e.g., 2-ethoxyl [nafcillin])

of 18
 Steric factors that assure β-lactamase resistance, however, do not necessarily
also confer stability to acid. As Methicillin> penicillin G (more labile to acid-
catalyzed hydrolysis).
 Bulkier substituents are required to confer effective beta-lactamase
resistance among five-membered–ring heterocyclic derivatives.
o Thus, members of the 4-isoxazoyl penicillin family (e.g., oxacillin,
cloxacillin, and dicloxacillin) require both the 3-aryl and 5-methyl
(3-methyl and 5-aryl) substituents for effectiveness against beta-
lactamase–producing S. aureus.
o The isoxazoyl penicillins, particularly those with an electronegative
substituent in the 3-phenyl group (cloxacillin, dicloxacillin, and
floxacillin), are also resistant to acid-catalyzed hydrolysis of the beta-
lactam, for the reasons described previously.
(Bulkier substituents- five-membered–ring effectiveness against beta-lactamase–producing S.
aureus)
 The β-lactamase–resistant penicillins tend to be comparatively lipophilic
molecules that do not penetrate well into Gram-negative bacteria.
 The same amino group that enhanced stability in acidic conditions also results
in their relatively poor absorbance through the walls of the GI.
 and as a result diarrhoea is a common side effect, as they will act upon and
diminish the numbers of essential bacteria present in the intestines.
 For penicillin derivatives in general it has been found that hydrophobic side
chains asserts
o good activity against G+ve bacteria (ex)
o but poor activity against G-ve strains (ex)
 For penicillins containing hydrophilic side chains the reverse is true;
o good activity is observed against G-ve bacteria and
o relatively poor activity against G+ve species.
Β- lactamase resistance against S aureus
Yes No
Methi, Nafi, Oxa, Cloxa,
Diclo
PC-G, PC-V, Ampi, amoxy,
Carben, Ticarci, Mezlo, Pipara

of 18
3.2.c Extended-Spectrum Penicillins
Semi synthetic penicillins have provided significant advance by the following
manners
 The introduction of an ionized or polar group into the α-position of the side
chain benzyl carbon atom of penicillin G confers activity against G-ve bacilli.
 Hence, derivatives with an ionized α-amino group, such as ampicillin and
amoxicillin, are generally effective against such
o G-ve genera as
o Escherichia, Klebsiella, Haemophilus, Salmonella, Shigella, &
o non–indole-producing Proteus.
o Furthermore, activity against penicillin G–sensitive, G+ve species is
largely retained.
 The introduction of α-amino group in ampicillin (or amoxicillin) creates an
additional chiral centre, which extends spectrum of activity.
o Extension of the antibacterial spectrum applies only to the D-isomer
>L-isomer or benzylpenicillin (which are equiactive) against various
species of the aforementioned genera of G-ve bacilli (D>L 2-8 times).
o Hydrophilic penicillins, such as ampicillin, penetrate G-ve bacteria
more readily than penicillin G, penicillin V, or methicillin.
o α-Hydroxy substitution also yields “expanded-spectrum” penicillins
with activity and stereoselectivity similar to that of the ampicillin group.
o Note that α-amino benzyl penicillins exist as zwitterions over a
broad pH range and, as such, are considerably less polar than
carbenicillin.
 Incorporation of an acidic substituent at the α-benzyl carbon atom of PC-G
o imparts clinical effectiveness against G-ve bacilli
o extends the spectrum of activity (against organisms resistant to
ampicillin).
 Thus, α-carboxybenzylpenicillin (carbenicillin) is active against
o ampicillin-sensitive, G-ve species and
o additional G-ve bacilli of the genera Pseudomonas, Klebsiella,
Enterobacter, indole-producing Proteus, Serratia, and Providencia.

of 18
o Carbenicillin is active against both β-lactamase–producing and non–β-
lactamase-producing strains of G-ve bacteria.
o The potency of carbenicillin against most species of penicillin G-
sensitive, G+ve bacteria is several orders of magnitude lower than that
of either penicillin G or ampicillin; (carbe<PC-G & Ampi)
o presumably because of poorer penetration of a more highly ionized
molecule into these bacteria.
o This increased polarity is apparently an advantage for the
penetration of carbenicillin through the cell envelope of G-ve
bacteria.
 This selective penetration of ampi, amoxi & carbenicillin is believed to take
place through the porin channels of the cell membrane.
 A series of α-acylureido–substituted penicillins, exemplified by, exhibit
greater activity against certain G-ve bacilli than carbenicillin.
oThe acylureidopenicillins are, however, superior to carbenicillin against
Klebsiella spp., Enterobacter spp., and P. aeruginosa.
oMore facile penetration through the cell envelope of these particular
bacterial species is the most likely explanation for the greater potency.
oThe acylureidopenicillins, unlike ampicillin, are unstable under acidic
conditions; therefore, they are not available for oral administration.

of 18
Table:-Summarised SAR of penicillin’s for Extended spectrum of activity
Name of PC Structural change Change in activity
Ampicillin &
amoxicillin,
ionized α-amino group are generally effective against such
G-ve genera as Escherichia, Klebsiella,
Haemophilus, Salmonella, Shigella, and
non–indole-producing Proteus.
Ampicillin α-amino group creates
an additional chiral
center.
D-isomer, > L-isomer or benzylpenicillin
(2-8 times)
Hydrophilic penicillins, penetrate G-ve bacteria > penicillin G,
V, or methicillin
Amoxicillin α-OH substitution also
yields
“expanded-spectrum” with activity and
stereoselectivity similar to that
of the ampicillin group
Ampi> amoxy (2-5 times more active & acid stable)
Carbenicillin
α-Carboxybenzyl
penicillin
Incorporation of an
acidic substituent at
the α-benzyl carbon
atom of penicillin G
also imparts clinical effectiveness
against G-ve bacilli &, furthermore,
extends the spectrum of activity to
include organisms resistant to ampicillin.
Active against ampicillin-sensitive, G-ve
species & G-ve bacilli of the genera
Pseudomonas, Klebsiella, Enterobacter,
indole-producing Proteus, Serratia, &
Providencia.
active against both β-lactamase–
producing & non–β-lactamase-producing
strains of G-ve bacteria.
Against most species of penicillin G-sensitive, G+ve bacteria
 penicillin G or ampicillin,> carbenicillin (is several orders of magnitude lower)
 presumably because of poorer penetration of a more highly ionized molecule
into these bacteria.
azlocillin,
mezlocillin, and
piperacillin
α-acylureido–
substituted penicillins,
Exhibit greater activity against certain
Gram-ve bacilli than carbenicillin; More
facile penetration through the cell
envelope
azlocillin, mezlocillin, and piperacillin> carbenicillin (certain G-ve bacilli)

of 18
MOA (PBP & D-alanine cross linking)
 Penicillins have a structural resemblance to two D-alanine residues linked
together, and
 are mistaken by the transpeptidase enzyme for D-Ala-D-Ala, and thus
incorporated into the active site.
 Once bound, the b-lactam carbonyl is attacked by the serine hydroxyl, and
ring opening occurs to leave the penicillin covalently bound to the enzyme.
 The bulky thiazolidene ring now blocks access to the active site by either a
pentaglycine chain or water. As a result the penicillin becomes irreversibly
bound to the transpeptidase enzyme, preventing it from functioning properly.
 This results in incomplete cell walls that are much more fragile and porous,
and eventually lead to swelling followed by cell lysis and death.
 All β-lactam antibiotics* binds to PBPs, which are requisite for cell
wall synthesis of bacteria. PBPs are members of transpeptidases (a subgroup
of enzymes).
Table:- Different classes of PBP’s & their role in bacterial cell wall synthesis/
formation
PBP class/
PBM
Type of enzyme Role Result of inhibition
PBPs 1a &1b-
first-generation
cephalosporins
Transpeptidases
in peptidoglycan
synthesis associated with
cell elongation
results in spheroplast
formation & rapid cell
lysis-
PBP 2-
Amdinocillin
only to PBP -2
CP’S
involved in maintaining
the rod
shape of bacilli
results in ovoid /round
forms that undergo
delayed lysis
PBP 3????-
Doubtful-
whether
inhibition of
PBP 3 is
lethal to
bacterium.
PC-G & CP’S
required for septum
formation
during cell division
in the formation of
filamentous forms
containing rod-shaped
units that cannot
separate.
PBPs 4 through
6
Carboxypeptidases
responsible for
the hydrolysis of D-
alanine–D-alanine
terminal peptide
bonds of the cross-linking
peptides
Apparently not lethal to
the bacterium, even
though cleavage of the
terminal D-alanine bond
is required before
peptide cross-linkage.

of 18
Unit of activity measurement
Penicillin Units for assay
1. The commonly known unit value to measure the activity is the Oxford unit:
1 Oxford unit is defined as the smallest amount of penicillin that will show the
ability to inhibit (in vitro), the growth of a strain of Staphylococcus in 50 mL of
culture medium under specified experimental conditions.
2. The other is United States Pharmacopoeia (USP) defines unit as the
antibiotic activity of 0.6 µg of penicillin G sodium reference standard.
The weight to unit correlation of the penicillin differs/changes with the acyl
substituent and with the salt formed of the free acid, accordingly-
Penicillin salt form of the free acid equivalent to units
1 mg of penicillin G sodium 1,667
1 mg of penicillin G procaine 1,009
1 mg of penicillin G potassium 1,530
Precautions
(Drug-drug interaction/ Drug excipients interaction & allergy)
Because penicillins are inactivated by metal ions such as zinc and copper, it has
been suggested that the phosphates and the citrates combine with these metals to
prevent their existence as free ions in solution
Combination of penicillin & aminoglycoside {PC & AG}
(Good but be careful!!!!!)
 The low toxicity of carbenicillin (and the penicillins in general), however,
usually permits (in the absence of allergy) the use of such high doses without
untoward effects.
 Furthermore, carbenicillin (and other penicillins), when combined with
aminoglycosides,
o exerts a synergistic bactericidal action against bacterial species
sensitive to both agents, frequently allowing the use of a lower dose

of 18
of the more toxic aminoglycoside than is normally required for
treatment of a life-threatening infection.
o The chemical incompatibility of penicillins and aminoglycosides
requires that the two antibiotics be administered separately;
otherwise, both are inactivated.
o It has been showed that acylation of amino groups in the
aminoglycoside by the β-lactam of the penicillin occurs.
Combination of penicillin & clavulinic acid {PC & CA}
Combination of penicillin & lactobacillus {PC & LB}

Penicillins by Dr M H Ghante.pdf

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Penicillins by Dr M H Ghante.pdf

Similar to Penicillins by Dr M H Ghante.pdf (20)

More from Mahavir Ghante

More from Mahavir Ghante (9)

Recently uploaded

Recently uploaded (20)

Penicillins by Dr M H Ghante.pdf