Prof. Dr. Ravisankar

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BETA LACTAM ANTIBIOTICS
VIGNAN PHARMACY COLLEGE, Vadlamudi,Guntur ,(A.P)
Dr. P. Ravisankar
M. Pharm., Ph.D.
PROFESSOR and HOD

 BETA-LACTAM ANTIBIOTICS
• Introduction
• Historical Background
• Classification
 PENCILLINS
• Introduction
• Classification
• Structural Activity Relationship
• Mechanism of Action
 CEPHALOSPORINS
• Introduction
• Classification
• Mechanism of Action
 CARBAPENEMS
• Introduction
 MONOBACTAMS
• Introduction
 Key points
 Conclcsion
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
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 The name “Lactam” is given to cyclic amides and is analogous to
the name “Lactone” which is given to cyclic esters .
 Antibiotics that contains the β-lactam (a four membered cyclic
amide) ring structure constitute the dominant class of agent
currently employed for the chemotherapy of bacterial infections.
 β-lactam are the most widely used group of antibiotics available.
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 3
INTRODUCTION

 The first synthetic β-Lactam was prepared
by HERMANN STAUDINGER in 1907
by reaction of the schiff base of aniline and
benzaldehyde with diphenylketone in a
cycloaddition.
 Upto 1970, most β-Lactam research was
concerned with the penicillin and cephalosporin
groups, but since then a wide variety of structures have been
described.
HISTROICAL BACKGROUND

CLASSFICATION OF β-LACTAM ANTIBIOTICS

1
• Beta Lactam antibiotics are indicated for the prophylaxis
and treatment of bacterial infections caused by
susceptible organisms.
2
• Traditionally Beta Lactam antibiotics were mainly active
only against gram positive bacteria
3
• The beta lactam antibiotics active against various gram
negative organisms has increased their usefulness
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR.
(A.P) 6
CLINICAL USES

VIGNAN PHARMACY COLLEGE,
VADALAMUDI,GUNTUR. (A.P)7
ADVERSE
EFFECTS
fever
angioedema
nausea
dermatitis
erythema
rashes
diarrhea
vomiting

PENICILLINS:
 It is an antibiotic, discovered by Alexander
Fleming(1881-1955) in 1928.
 β-lactam antibiotics
 It was isolated from fungus
Penicillium notatum.
Alexander Fleming
(Penicillium notatum)

 Florey and Chain isolated penicillin by
freeze drying and chromatography.
 Penicillin was effective even when it is
diluted up to 800 times.
Biological sources:
Penicillium notatum, Penicillium chrysogenum
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Fleming’s famous petridish
Penicillium chrysogenum

BASIC STRUCTURE OF PENICILLIN:
VADALAMUDI,GUNTUR. (A.P)
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Acyl amino side chain
6-Amino
penicillanic
acid
H
C
C N
H
C
C
C
S
O
CH3
CH3
COO-
H
HNCR
O
Free carboxylate
Cis stereochemistry
Most reactive carbonyl group
Site of Penicillinase action
Basic chemistry:Beta lactum ring+Thiazolidine ring
Bicyclic ring system sysyem is essential
Variable group
Beta lactum ring
Thiazolidine ring
Methyl groups

Classification of Penicillins
Natural penicillins β- lactamase resistant
penicillins
Aminopenicillins Carboxypenicillins Ureidopenicillins
-Penicillin G
-Penicillin V
-Methicillin
-Nafacillin
-Isoxazolyl Penicillins
-Ampicillin
-Amoxicillin
-Ticarcillin -Piperacillin
-Mezlocillin
-Azlocillin
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PENICILLIN G (BENZYL PENICILLIN)
 Acid unstable.
 Parenteral route.
 Self destructive mechanism in its
structure because of influence of acyl side chain.
(A.P)
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N
S
CH3
CH3
COOH
O
HNCH2C
O
H H
H
PENICILLIN DERIVATIVES

PENICILLIN V
 More acid stable than Penicillin G.
 Administered by oral route.
 Electron withdrawing group is present in
acyl side chain.
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N
S
CH3
CH3
COOH
O
HNCH2C
O
O
H H

METHICILLIN:
 Has no electron withdrawing group
on the side chain.
 Acid sensitive and has to be injected.
 Steric shields can be added to penicillins to
protect from penicillinase enzyme.
N
S
CH3
CH3
COOH
O
HNC
O
H H
H
CH3
CH3

O
N
SNH
COOH
CH3
CH3
C
O
ISOXAZOLYL PENICILLINS
O
N
CH3
R1
R2
R1 R2
Oxacillin H H
Cloxacillin Cl H
Dicloxacillin Cl Cl
Better penicillinase resistant agents have been
developed.
The isoxazolyl ring acts as the steric shield but
It is also electron-withdrawing giving the
Structure acid stability.
Flucloxacillin Cl F
Bulky and electron
withdrawing

AMPICILLIN:
 If hydrophilic groups like
(NH2, OH , COOH ) are attached
to the carbon that is α to the carbonyl group
on the side chain then α hydrophilic group aids
the passage of penicillins through porins of gram –ve bacteria.
 Acid stable
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N
S
CH3
CH3
COOH
O
HNC
H H
HC
O
H
NH2

AMOXICILLIN:
 β hydroxy ampicillin.
 Same spectrum of activity as that of penicillin G but more
active against gram–ve bacteria.
 Acid resistant hence given orally.
 Non toxic.
N
S
CH3
CH3
COOH
O
HNC
H H
HC
O
H
NH2
HO

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STRUCTURALACTIVITY RELATIONSHIP :
1
2
3
4
56
7

Bacteristatic
Antibiotics
Bactericidal
Penicillins
Inhibit the synthesis of peptidoglycon layer containing NAM &NAG
connected by penicillin binding proteins(PBP)
Acts on PBP and inhibits the synthesis of Peptidoglycon.
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MECHANISM OF ACTION:
Gram +ve Gram -ve
Cell membrane
Peptidoglycon
cell wall
Lipopolysacc
haride layer

(Peptidoglycan cell wall)
N-acetylglucosamine
N-acetylmuramic acid
Transpeptidases located
within the cell membrane
are responsible for
cross linking the
Peptidoglycan chains
Transpeptidases
(Penicillin Binding Proteins)
In order to make the rigid grid,
There is an enzyme called
Transpeptidase,which connects
the Little peptide strings
perpendicular to the NAM and
NAG chains.
Cell membrane
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(Cell membrane)
(Peptidoglycan cell wall)
Penicillin’s inactivate
the transpeptidase enzyme
by covalently bonding
to the serine residues
within the active site.
Bonding is by acetylation
Transpeptidases
(Penicillin Binding Proteins)
S
O
22

BETA LACTAMASE INHIBITORS:
 Has negligible antibacterial activity.
 Given with Penicillins which increases spectrum of activity.
 Microbial resistance to beta lactam antibiotics.
Beta lactamase

β lactam antibiotics β lactam antibiotics + β lactamase inhibitor
Contain β lactum ring Complex
Catalysing the
β lactamases hydrolysis of
β lactum ring Effectiveness of β lactamase is diminished
INACTIVE COMPOUNDS
Enhances the activity of β lactam
antibiotics

Clavulanic acid:
 Isolated from Streptomyces clavuligerus.
 1st naturally occurring β lactam ring that was not fused to a ‘S’
containing ring.
Sulbactum:
 β lactamase disabiling agent.
 Prepared by partial chemical synthesis
from penicillins.
N
O
O
H
COOH
H
H
OH
N
S
O COO-Na+
H
O
CH3
CH3
O
H

Tazobactum:
 Co-administered with Piperacillin.
 Has little or no antibacterial activity.
N
S
O COO-
O CH3
O
H
N
N
N
Beta lactamase Inhibitors:
Available agents β-lactamase binding Potency
Clavulanic acid + + + + + +
Sulbactam + + + + + +
Tazobactam + + + + + + + +

USES:
 Streptococcal infections
 Pneumococcal infections
 Meningococcal infections
 Gonorrhoea
 Syphilis
 Diphtheria
 Tetanus
TOXICITY:
 Nausea ,Dizziness ,Head ache ,skin rashes ,Bronchospasm ,
vasculitis , inflammation of blood vessles .
 Hypersensitivity or allergic reactions. 27

(A.P) 28

Cephalosporins are second major group of β-lactam ,broad
spectrum,penicillanase resistant antibiotics
 They were isolated from cultures of
Cephalosporium acremonium by italian scientist
Giuseppe Brotzu in 1945.
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INTRODUCTION

 In 1948, Abraham and his colleagues have isolated three principle
antibiotic components from cultures of fungus.
 1964 ,the first semi synthetic cephalosporin i.e. cefalothin was
launched in the Market by Eli Lilly and company.
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Cephalosporin P
Cephalosporin N
Cephalosporin C

CLASSFICATION OF CEPHALOSPORINS
First
Generation
Second
Generation
Third
Generation
Fourth
Generation
Fifth
Generation
1.Parenteral 1.Parenteral 1.Parenteral 1.Parenteral 1.Parenteral
Cephalothin Cefamycinc Cefotaxime Cefepime Ceftobiprole
Cephaloridine Cefoxitin Ceftazidime Cefpirome
Cefazolin Cefotitan Ceftriaxone
Cefmetazole
2.Oral 2.Oral 2.Oral
Cephalexin Cefachlor Cefixime
(Keflex) Cefprozil Cefdinir
Cephadroxil Ceftibuten
(Durecef)
3.Oral & Parenteral
Cephradine
31VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)

 These drugs are very active against Gram-positive cocci (such as
Pneumococci, Streptococci, and Staphylococci).
 They do not cross BBB.
1ST Generation Cephalosporins:

33
They have a greater gram-negative spectrum while retaining some activity
against gram-positive bacteria.
 They are also more resistant to β-lactamase.
No BBB Penetration.
2nd Generation Cephalosporins:

Expanded Gram-negative coverage
 Able to cross the BBB.
Anti-pseudomonal activity.
3rd Generation Cephalosporins:

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)35
 Zwitterionic compounds.
 Good affinity for the transpeptidase enzyme.
 Low affinity for some β-lactamases.
 Cross BBB and effective in meningitis.
4th Generation Cephalosporins:

36
CEFTOBIPROLE
 Active against
methicillin-resistant -Staphylococcus aureus
penicillin-resistant - Streptococcus pneumoniae
5th Generation Cephalosporins:

STRUCTURE -ACTIVITY RELATIONSHIP:
Basic chemistry:β-lactam ring+Dihydrothiazine ring
Variable group
Variable group7-Aminocephalosporanic acid

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Cephalosporins are bactericidal.
Cephalosporins and β-lactams bind to
PBPs(Penicillin Binding Proteins).
Some PBPs have transpeptidase
activity.
Transpeptidase activity is essential
in cell wall synthesis.
MECHANISM OF ACTION:

USES:
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Adverse effects:
Disulfiram- like effect
Nephrotoxicity
Bleeding
Allergic reactions
Phlebitis
IMPETIGO CELLULITIS P.aeruginosaINFECTIONS
PNEUMONIA BACTERIAL MENINGITIS

Cephalosporins advantages over penicillins:
 Increased acid stability compare to penicillins.
 Most of the drugs have better absorption than penicillins.
 Broad antimicrobial spectrum.
 Increased activity against resistant microorganisms.
 Decreased allergenicity.
 Increased tolerence than penicillins.

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 Carbapenems are a class of β-lactam antibiotics with a broad spectrum
of antibacterial activity.
 They have a structure that renders them highly resistant to most
β-lactamases.
 Carbapenem antibiotics were originally developed from the carbapenem
thienamycin, a naturally derived product of Streptomyces cattleya
Examples
Imipenem, Meropenem, Ertapenem
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INTRODUCTION

IMIPENEM:
 IMIPENEM has a wide spectrum with
good activity many gram negative rods
incluiding P.aeruginosa, gram positive organisms and anaerobes.
 Imipenem is inactivated by dehydropeptidases in renal tubules,
result in low urinary concentrations.
(Imipenem)

Carbapenems which tend to be more common with imipenem are nausea,
vomiting, diarrhea, skin rashes, and reactions at the infusion sites
Excessive levels of imipenem in patients with renal failure may lead to
seizures
Patients allergic to penicillins may be allergic to carbapenems.
ADVERSE EFFECTS

(A.P) 45

INTRODUCTION
 Monobactams are drugs with a monocyclic β-lactam ring.
 They are relatively resistant to beta-lactamases and active aganist
Gram-negative rods (including Pseudomonas and Serratia).
 They have no activity against Gram-positive bacteria or anaerobes.
Examples
Aztreonam , Tigemonam.

AZTREONAM
 Aztreonam is given i.v.
 The half-life is 1–2 hours and is greatly prolonged in renal failure.
 Penicillin-allergic patients tolerate aztreonam
without reaction
(Aztreonam)

KEYPOINTS:
 Penicillins have a bicyclic structure consisting of a β-lactam
ring fused to a Thiazolidine ring.
 Penicillin can be made more resistant to acid conditions by
incorporating an electron withdrawing group into the acyl
side chain.
 Broad spectrum activity is associated with the presence of an
α-hydrophilic group on the acyl side chain of penicillins.
 Cephalosporins contain a strained β-lactam ring fused to a
dihydrothiazine ring.
 Semi-synthetic cephalosporins can be prepared from
7- aminocephalosporanic acid.
 Methyl substitution at the 3-position of cephalosporins is
good for oral absorption.

 Beta lactam antibiotics are useful and frequently prescribed
antibiotics that share a common structure.
 Bacterial resistance against the beta lactam antibiotics continues
to increase at a dramatic rate.
 Therapy with beta lactam antibiotics is a dynamic that
prevalence of bacterial resistance to these agents continues to
rise, while new and more effective agent are released for clinical
use.
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Conclusion:

 William O. Foye.,Textbook of Medicinal Chemistry,Pg no: 1089 -1106
 Sriram., Medicinal Chemistry, Pg no: 295-309.
 Kadam., Textbook of Medicinal Chemistry, Pg no: 68-82.
 Ilango., Principles of Medicinal chemistry(vol.1), Pg no: 121-143.
 G.L.Patrick., Introduction to Medicinal Chemistry, Pg no:388-415.
 Good man And Gil Man’s ;The Pharmacology Basis Of Therapeutics
Tenth Edition page no 1189-1225.
 JH Block & JM Beale., Wilson & Giswold’s Textbook of Organic
Medicinal Chemistry & pharmaceutical chemistry 11th Edition, 2004.
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Reference:

Prof. Dr. Ravisankar

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