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COURSE NAME: MC-III
COURSE CODE: 20PY3227T
Topic:
ΒETA LACTAM ANTIBIOTICS
Department of Pharmacy
Session - 2
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AIM OF THE SESSION
To familiarize students with the basic concept of antibiotics and its Historical background, Nomenclature,
stereochemistry.
INSTRUCTIONAL OBJECTIVES
This Session is designed to:
1. Demonstrate about the antibiotics
2. Describe about the chemistry of antibiotics
3. List out the drugs used in antibiotics
4. Describe the SAR of different antibiotics
LEARNING OUTCOMES
At the end of this session, you should be able to:
1. Define the term antibiotics
2. Describe the chemistry of antibiotics
3. Summarize the chemistry of antibiotics
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• β-lactam antibiotics are Bacteriostatic at low concentrations and Bactericidal at high concentrations.
• They exhibit Potent and rapid bactericidal action against bacteria especially during the growth phase
• They selective low frequency of toxicity and other adverse effects towards host makes them Popular
agents of choice in Curing various bacterial infections.
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Classification of β-lactam antibiotics
The various class of antibiotics with examples and structures are as follows:
1. Penicillin's
2. Cephalosporins
3. Monobactams
4. Carbapenems
5. Carbacephems
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Penicillin's
• Penicillin was the first antibiotic to be used clinically in the treatment of pathogenic diseases.
• It was discovered as a natural product obtained from the moulds of Penicillium genus. It is a
member of a broad glass of beta lactam antibiotics that include Cephalosporins, Monobactams,
Carbapenems and beta lactamase inhibitors.
• The common structural features of all the beta lactam antibiotics is the presence of a beta lactam
nucleus in their molecular structure.
• Structural modifications in the basic penicillin molecule has led to the development of synthetic
and semi synthetic
• Penicillin's which shows an extended spectrum of antibacterial activity against certain Gram –
negative bacteria also
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Mechanism of action of Penicillins
• Penicillins inhibits transpeptidation by covalently binding to penicillin binding proteins
(PBPs) and inactivating them.
• As a result , an imperfect bacterial cell wall is formed which is weak in nature and
susceptible to lysis by solutes in the Surrounding medium.
• In addition to the above action , Penicillin's also causes activation of autolyzing enzymes
called murein hydrolase which initiates cell lysis and causes cell death.
• Therefore , penicillin's are bactericidal drugs that not only inhibit cell wall synthesis but
also causes bacterial lysis.
• Since cell wall synthesis occurs in the growth phase, penicillins are active against rapidly
multiplying bacteria.
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• Penicillins are more effective against Gram positive bacteria than Gram negative
bacteria due to the difference in the composition of cell wall of both these bacteria.
• In Gram positive bacteria the cell wall is directly exposed to the external conditions,
which makes it easier for the drugs to gain access and inhibit the transpeptidation.
• On the other hand cell wall in Gram negative bacteria is covered by an outer
membrane which contains porin channels.
• These channels function to allow the passage of selective substances only .Hence access
to the bacterial cell wall by penicillins gets restricted.
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Nomenclature
6-amino-penicillanic acid(6-APA)
• The basic structure of penicillin consists of a thiazolidine ring (A) fused to a Beta lactam ring
(B) to which an amino group is attached at the 6th position .
• This entire moiety is called 6-aminopenicillanic acid( 6-APA).It is the activity moiety of the
penicillin structure responsible for antibacterial activity.
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• Substitution of one hydrogen in NH2 group with acyl amino side chain (RCONH) resulted in
penicillins. Thus , penicillins are substituted 6-amino penicillanic acid
• Any structural , chemical or metabolic alterations in this nucleus influences the antibacterial
activity.
• The chemical nature of the side chain determines the antimicrobial spectrum as well as the
pharmacokinetics and pharmacological properties of the resulting penicillins
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• Natural penicillin (i.e.,) penicillin G consists of a phenylmethyl (C6H5CH2) group in the side chain
(R).
Penicillin G
• It has the greatest antibacterial activity and is the only natural penicillin clinically in use.
• Semisynthetic penicillins were prepared by splitting the amide linkage between the 6-APA molecule
and the side chain of the natural penicillin.
• This led to the formation of free 6-APA moiety to which various side chains were added to produce
the currently used semisynthetic penicillins.
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• Hence , in semisynthetic penicillin's, R is anything other than the phenylmethyl group.
• Ampicillin was the first semisynthetic derived penicillin.
Ampicillin
• It is prototype semisynthetic penicillin prepared by replacing one of the hydrogen atoms of
the methylene group of penicillin G with an amino group.
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Systems of Nomenclature
• Nomenclature or naming of penicillins is a complex task accomplished to the following different systems.
Chemical abstract (CA) system
• According to this system penicillin are numbered starting from the sulphur atom. Sulphur is assigned the 1st
position, while the nitrogen is assigned the 4th position.
• Therefore according to this system, penicillin's are named as 6-acyl amino -2,2-dimethyl-3-carboxylic acid
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Systems of Nomenclature
• Nomenclature or naming of penicillins is a complex task accomplished to the following different systems.
United States Pharmacopoeia (USP) system
• The USP system of naming penicillin's is the reverse of CA system. According to it the nitrogen atom is given the
1st position , while sulphur atom is assigned the 4th position.
• Therefore according to this system, penicillin's are named as 4-thia-1 azabicyclic heptane.
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Systems of Nomenclature
• Nomenclature or naming of penicillins is a complex task accomplished to the following different systems.
As derivatives of Penam
• In order to simplify the naming of penicillin's , a more simple form of nomenclature was adopted.
• Here, the unsubstituted bicyclic system together with the carbonyl group has been named as penam.
• Therefore according to this system of nomenclature penicillin's are 4-thia-1-azabicyclo –heptane-7-one
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Systems of Nomenclature
• Nomenclature or naming of penicillins is a complex task accomplished to the following different systems.
As derivatives of Penicillanic acid
• In this method penicillin's are named as derivatives of penicillanic acid.
• According to this system penicillin's consists of penicillanic acid ring system with 2,2-dimethyl and carboxyl
groups as substituents at positions 2 and 3 respectively
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Systems of Nomenclature
• This is the most trivial of all naming system. In this system the entire 6-carbonyl amino penicillanic acid(6-carbonyl-
APA) Portion of the molecule is named as penicillin and the different penicillins are distinguished based on the R
group on the amino acyl side chain As derivatives of Penicillins
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SAR of Beta lactam antibiotics
• Beta lactam antibiotics contain beta-lactam ring which is a tetracyclic amide
• Beta lactam ring is fused to a second heterocyclic ring(5-memberd ring).
• Difference in the structure of the second heterocyclic ring results in various types of β-lactam antibiotics.
• Presence of Carbonyl group(C=O) in β-lactam ring is a common feature of all the antibiotics and is essential for
antibacterial activity.
• Removal or Substitution of Nitrogen atom in β-lactam ring results in inactive compounds.
SAR of Beta lactam antibiotics
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Mechanism of Action of Beta-lactam Antibiotics
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General Mechanism of Action
• The bacterial cell wall which encloses the bacterial cell- performs four main functions.
• Firstly, it acts as a semipermeable it allows only a selected range of substances to enter into the
cell from its surrounding environment.
• Secondly the cell wall functions to maintain the integrity of the cell from the osmotic changes
present in the external surroundings.
• Thirdly, the normal growth and development of bacteria is predominantly due to bacterial cell
wall.
• Lastly, the enzymes of host that can digest the bacterial cell are inactivated by the bacterial cell
wall.
• Moreover, a group of proteins termed penicillin binding proteins(PBPs) have been involved in the
biosynthesis and remodelling of peptidoglycan. These enzymes are located in the cytoplasmic
cell membrane which is present below peptidoglycan layer. These PBPs are the major targets of
ß-lactam antibiotics.
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Mechanism of action of Beta lactam antibiotics
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Stereochemistry of penicillin's
• Penicillin comprise of three chiral carbon atoms they are C-3, C-5 and C-6. Maximum all synthetic and
semisynthetic penicillin's etic consists of similar absolute configuration as these three atoms
• chiral carbon centers are carbon atoms that are attached to four different substituents, that are placed at the
corners of a tetrahedron. Chiral carbon atoms are also referred to as 'stereogenic carbons' or 'asymmetrical carbon
atoms'.
• The chiral carbon atom with acylamino group exhibits L . Configuration and with carboxyl group it exhibits
Deconfiguration.
• Therefore these two groups are trans to one another with acyl amino group being in α- orientation , where as
carboxyl group In β-orientation , both in respective to penam ring system.
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SAR of penicillin's
• Benzylpenicillin has a narrow spectrum of activity. It undergo degradation on treatment with acid and alkali and is
suspectable to almost all the β –lactams.
• To overcome these limitations some structural modifications were carried out in the 6-APA moiety which results in
several semisynthetic penicillin's having superior properties.
• The stability as well as spectrum of activity of the resultant penicillin's were greatly influenced by the chemical
substituents attached to the penicillin nucleus.
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1.Modification at 6-Acyl side chain
A) In Substituting the α –carbon of the side chain with groups like amino (as in ampicillin) , guanidine or chloro
resulted agents having good resistivity towards acidic degradation.
B) Substituting the acyl side chain with an α – aryloxy alkyl group gave penicillin's having good acid stability and oral
absorption.
C) Introduction of a polar or ionized group like amino ,hydroxyl, carboxyl and sulfonyl at α-carbon atom of
benzylpenicillin resulted in agents having antibacterial activity against Gram –negative bacteria.
D) Replacement of the acyl sidechain with hydroxymethyl group showed an increase in the antibiotic activity
against Gram –negative bacteria.
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ACTIVITIES/ CASE STUDIES/ IMPORTANT FACTS RELATED TO THE
SESSION
• Prepare a case study regarding the usage of combination of different antibiotics.
Reason for combinational usage
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SUMMARY
• Importance of beta lactam ring in the mechanism of action of antibiotics
• SAR of beta lactam antibiotics
• Introduction to penicillin's
• Different systems of nomenclature in penicillin's
• Mechanism of action of penicillin's
• SAR of penicillin's
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SELF-ASSESSMENT QUESTIONS
1. What is the basic functional structure of Penicillin?
(a) Thiazolidine ring
(b) Phenyl ring
(c) Beta lactam ring.
(d) Cepham ring
2. Bacterial cytoplasmic membrane proteins that act as the initial receptors for penicillin’s and other
beta-lactam antibiotics
(a) Cephalosporin binding protein
(b) Monobactams
(c) Penicillin Binding Protein.
(d) Aminoglycosides
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TERMINAL QUESTIONS
1. Describe the nomenclature of penicillin's
2. List out the different systems of nomenclature of penicillin's
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REFERENCES FOR FURTHER LEARNING OF THE SESSION
Reference Books:
1. Wilson and Griswold's Organic medicinal and Pharmaceutical Chemistry.
2. Burger’s Medicinal Chemistry, Vol I to IV.
3. Remington’s Pharmaceutical Sciences.
Sites and Web links:
1.
2.
3.
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THANK YOU
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