Beta Lactam Antibiotics

BETA LACTAM ANTIBIOTICS
Dr. P. Ravisankar
M. Pharm., Ph.D.
PROFESSOR and HOD
VIGNAN PHARMACY COLLEGE, Vadlamudi,Guntur ,(A.P)1

 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
2
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
INTRODUCTION
 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

HISTROICAL BACKGROUND
 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.

CLASSFICATION OF β-LACTAM ANTIBIOTICS

CLINICAL USES
• Beta Lactam antibiotics are indicated for the prophylaxis

and treatment of bacterial infections caused by
1 susceptible organisms.
• Traditionally Beta Lactam antibiotics were mainly active

2 only against gram positive bacteria
• The beta lactam antibiotics active against various gram

3 negative organisms has increased their usefulness
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR.

(A.P) 6
fever
nausea vomiting
angioedema ADVERSE diarrhea

EFFECTS
dermatitis rashes
erythema
VIGNAN PHARMACY COLLEGE,

7 VADALAMUDI,GUNTUR. (A.P)
PENICILLINS:
 It is an antibiotic, discovered by Alexander

Fleming(1881-1955) in 1928.
 β-lactam antibiotics
 It was isolated from fungus Alexander Fleming
Penicillium notatum.
(Penicillium notatum)
 Florey and Chain isolated penicillin by
freeze drying and chromatography.
 Penicillin was effective even when it is

diluted up to 800 times.
Fleming’s famous petridish
Biological sources:
Penicillium notatum, Penicillium chrysogenum
Penicillium chrysogenum
10
BASIC STRUCTURE OF PENICILLIN:
Basic chemistry:Beta lactum ring+Thiazolidine ring
Acyl amino side chain Cis stereochemistry
Thiazolidine ring
Methyl groups
H H S CH 3
R C HN C C
C CH 3
6-Amino
Variable group penicillanic
O C N
C H acid
O
Beta lactum ring
COO- Free carboxylate
Bicyclic ring system sysyem is essential
Site of Penicillinase action
Most reactive carbonyl group
11 VIGNAN PHARMACY COLLEGE,

VADALAMUDI,GUNTUR. (A.P)
Classification of Penicillins
Natural penicillins β- lactamase resistant Aminopenicillins Carboxypenicillins Ureidopenicillins

penicillins
-Penicillin G -Ampicillin -Ticarcillin -Piperacillin
-Methicillin
-Penicillin V -Amoxicillin -Mezlocillin
-Nafacillin
-Azlocillin
-Isoxazolyl Penicillins
12

PENICILLIN DERIVATIVES
PENICILLIN G (BENZYL PENICILLIN)

 Acid unstable. H H
H 2C C HN
S CH3
 Parenteral route.
O
CH 3
 Self destructive mechanism in its N
O H
structure because of influence of acyl side chain. COOH

(A.P)
13
PENICILLIN V
H H
O H 2C C HN
S CH3
O
CH 3
 More acid stable than Penicillin G. N
O
 Administered by oral route. COOH
 Electron withdrawing group is present in

acyl side chain.
14
taken IV OR IM
METHICILLIN:
CH 3
H H
 Has no electron withdrawing group C HN
S CH3
O
on the side chain. CH 3
CH 3 N
 Acid sensitive and has to be injected. O H

COOH
 Steric shields can be added to penicillins to
protect from penicillinase enzyme.

ISOXAZOLYL PENICILLINS
Bulky and electron
withdrawing
CH3
O
N O
R2 C NH S CH3
CH3
R1
N
O COOH
R1 R2
Better penicillinase resistant agents have been
Oxacillin H H developed.
Cloxacillin Cl H The isoxazolyl ring acts as the steric shield but
Dicloxacillin Cl Cl It is also electron-withdrawing giving the
Structure acid stability.
Flucloxacillin Cl F
AMPICILLIN:
O
 If hydrophilic groups like H H
HC C HN
S CH 3
(NH2, OH , COOH ) are attached NH 2

CH 3
N
to the carbon that is α to the carbonyl group O H

COOH
on the side chain then α hydrophilic group aids
the passage of penicillins through porins of gram –ve bacteria.
 Acid stable
17
AMOXICILLIN:
O
H H
HO HC C HN
S CH 3
NH 2
CH 3
 β hydroxy ampicillin. N
O H
COOH
 Same spectrum of activity as that of penicillin G but more
active against gram–ve bacteria.
 Acid resistant hence given orally.
 Non toxic.
18
STRUCTURAL ACTIVITY RELATIONSHIP :
4
6 5
3
7 1
2
VIGNAN PHARMACY COLLEGE, 19

MECHANISM OF ACTION:
Gram +ve Gram -ve
Bacteristatic
Antibiotics
Bactericidal
Cell membrane
Lipopolysacc
Peptidoglycon haride layer
Penicillins cell wall
Inhibit the synthesis of peptidoglycon layer containing NAM &NAG

connected by penicillin binding proteins(PBP)
Acts on PBP and inhibits the synthesis of Peptidoglycon.

20
(Peptidoglycan cell wall)
Transpeptidases located
within the cell membrane
are responsible for
cross linking the
Peptidoglycan chains
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.
Transpeptidases
(Penicillin Binding Proteins)
Cell membrane
N-acetylglucosamine
N-acetylmuramic acid
21
(Peptidoglycan cell wall)
Penicillin’s inactivate
S the transpeptidase enzyme
by covalently bonding
O to the serine residues
within the active site.
Bonding is by acetylation
Transpeptidases
(Penicillin Binding Proteins)
(Cell membrane)

22
BETA LACTAMASE INHIBITORS:
Beta lactamase
 Has negligible antibacterial activity.
 Given with Penicillins which increases spectrum of activity.
 Microbial resistance to beta lactam antibiotics.

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

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

Tazobactum:
O
 Co-administered with Piperacillin. H
O CH3
S
 Has little or no antibacterial activity. N N

N
N
O COO-
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
INTRODUCTION
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.
29
 In 1948, Abraham and his colleagues have isolated three principle
antibiotic components from cultures of fungus.
Cephalosporin P
Cephalosporin N
Cephalosporin C
 1964 ,the first semi synthetic cephalosporin i.e. cefalothin was

launched in the Market by Eli Lilly and company.
30
CLASSFICATION OF CEPHALOSPORINS
First Second Third Fourth Fifth

Generation Generation Generation Generation Generation
generation 1 taken IV OR IM
1.Parenteral 1.Parenteral 1.Parenteral 1.Parenteral 1.Parenteral
Cephalothin Cefamycinc Cefotaxime Cefepime Ceftobiprole
Cephaloridine Cefoxitin Ceftazidime Cefpirome
used as sleeping pain injuctions
Cefazolin Cefotitan Ceftriaxone
Cefmetazole
2.Oral 2.Oral 2.Oral

Cephalexin Cefachlor Cefixime
(Keflex) Cefprozil Cefdinir
Cephadroxil Ceftibuten
(Durecef)
3.Oral & Parenteral

Cephradine
31
1ST Generation Cephalosporins:
 These drugs are very active against Gram-positive cocci (such as

Pneumococci, Streptococci, and Staphylococci).
 They do not cross BBB.
2nd Generation Cephalosporins:
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. 33
3rd Generation Cephalosporins:
Expanded Gram-negative coverage

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

5th Generation Cephalosporins:
if it works as antibiotics that

works on 30s or 50s ribosomical
anti synthetic protien or to
change DNA or stops follic acid
CEFTOBIPROLE
 Active against
methicillin-resistant -Staphylococcus aureus
penicillin-resistant - Streptococcus pneumoniae 36

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

MECHANISM OF ACTION:
Cephalosporins are bactericidal.

as its cidal its kill off the bacteria
Cephalosporins and β-lactams bind to
PBPs(Penicillin Binding Proteins).
Some PBPs have transpeptidase

activity.
Transpeptidase activity is essential

in cell wall synthesis.
38
USES:
IMPETIGO CELLULITIS P.aeruginosaINFECTIONS
PNEUMONIA BACTERIAL MENINGITIS
Adverse effects:
Disulfiram- like effect
Nephrotoxicity
Bleeding
Allergic reactions
Phlebitis 39

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.

41
INTRODUCTION
 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
42

IMIPENEM: (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.
43
ADVERSE EFFECTS
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.
44
(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.

Conclusion:
 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.
49

Reference:
 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.
50
51

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BETA LACTAM ANTIBIOTICS

VIGNAN PHARMACY COLLEGE, Vadlamudi,Guntur ,(A.P)1

 The name “Lactam” is given to cyclic amides and is analogous to

 Antibiotics that contains the β-lactam (a four membered cyclic

 β-lactam are the most widely used group of antibiotics available.

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 3

 The first synthetic β-Lactam was prepared

 Upto 1970, most β-Lactam research was

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 4

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 5

• Beta Lactam antibiotics are indicated for the prophylaxis

• Traditionally Beta Lactam antibiotics were mainly active

• The beta lactam antibiotics active against various gram

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR.

angioedema ADVERSE diarrhea

VIGNAN PHARMACY COLLEGE,

 It is an antibiotic, discovered by Alexander

 It was isolated from fungus Alexander Fleming

 Penicillin was effective even when it is

11 VIGNAN PHARMACY COLLEGE,

Natural penicillins β- lactamase resistant Aminopenicillins Carboxypenicillins Ureidopenicillins

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)

PENICILLIN G (BENZYL PENICILLIN)

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR.

 Electron withdrawing group is present in

 Acid sensitive and has to be injected. O H

protect from penicillinase enzyme.

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 15

(NH2, OH , COOH ) are attached NH 2

to the carbon that is α to the carbonyl group O H

on the side chain then α hydrophilic group aids

the passage of penicillins through porins of gram –ve bacteria.

 Acid resistant hence given orally.

VIGNAN PHARMACY COLLEGE, 19

Inhibit the synthesis of peptidoglycon layer containing NAM &NAG

Acts on PBP and inhibits the synthesis of Peptidoglycon.

VIGNAN PHARMACY COLLEGE,

 Given with Penicillins which increases spectrum of activity.

 Microbial resistance to beta lactam antibiotics.

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 23

Contain β lactum ring Complex

Enhances the activity of β lactam

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 24

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 25

 Has little or no antibacterial activity. N N

Beta lactamase Inhibitors:

Available agents β-lactamase binding Potency

Clavulanic acid ++ ++++

Tazobactam ++++ ++++

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 26

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)

Cephalosporins are second major group of β-lactam ,broad

 They were isolated from cultures of

 1964 ,the first semi synthetic cephalosporin i.e. cefalothin was

First Second Third Fourth Fifth

2.Oral 2.Oral 2.Oral

3.Oral & Parenteral

 These drugs are very active against Gram-positive cocci (such as

They have a greater gram-negative spectrum while retaining some activity

Expanded Gram-negative coverage

35 VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)

if it works as antibiotics that

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)

Basic chemistry:β-lactam ring+Dihydrothiazine ring