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

CONTENTS: 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) 2

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

NO

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

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CLASSFICATION OF β-LACTAM ANTIBIOTICS

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

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


CLINICAL USES

VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)7

ADVERSEEFFECTS

fever

angioedema

nausea

dermatitis

erythemarashes

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:


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Acyl amino side chain

6-Amino penicillanic acid

HC

C N

HC

C

C

S

O

CH3

CH3

COO-

H

HNCR

O

Free carboxylate

Cis stereochemistry

Most reactive carbonyl groupSite 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.


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.


N

S

CH3

CH3

COOH

O

HNCH2C

O

OH 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

HCH3

CH3

ON

SNH

COOH

CH3

CH3

C

O

ISOXAZOLYL PENICILLINS

ON

CH3

R1

R2

R1 R2

Oxacillin H HCloxacillin Cl HDicloxacillin Cl Cl

Better penicillinase resistant agents have been developed.The isoxazolyl ring acts as the steric shield butIt is also electron-withdrawing giving the Structure acid stability.Flucloxacillin Cl F

Bulky and electronwithdrawing


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


N

S

CH3

CH3

COOH

O

HNCH 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

HNCH H

HC

O

H

NH2

HO


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STRUCTURAL ACTIVITY RELATIONSHIP :

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3

4

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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. VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 20

MECHANISM OF ACTION: Gram +ve Gram -ve

Cell membrane

Peptidoglycon cell wall

Lipopolysaccharide layer


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(Peptidoglycan cell wall)

N-acetylglucosamine

N-acetylmuramic acid

Transpeptidases locatedwithin the cell membraneare responsible for cross linking thePeptidoglycan 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 inactivatethe transpeptidase enzymeby covalently bondingto the serine residues within the active site.

Bonding is by acetylation

Transpeptidases(Penicillin Binding Proteins)

S

O

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

NN

N

Beta lactamase Inhibitors:

Available agents β-lactamase binding Potency

Clavulanic acid + + + + + +

Sulbactam + + + + + +

Tazobactam + + + + + + + +

USES:

Streptococcal infections

Pneumococcal infections

Meningococcal infections

Gonorrhoea

Syphilis

Diphtheria

TetanusTOXICITY:

Nausea ,Dizziness ,Head ache ,skin rashes ,Bronchospasm , vasculitis ,

inflammation of blood vessles .

Hypersensitivity or allergic reactions.27


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CEPHALOSPORINS


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.


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.


Cephalosporin PCephalosporin NCephalosporin C

CLASSFICATION OF CEPHALOSPORINS

FirstGeneration

SecondGeneration

ThirdGeneration

FourthGeneration

FifthGeneration

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:


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:

34VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)

Expanded Gram-negative coverage Able to cross the BBB. Anti-pseudomonal activity.

3rd Generation Cephalosporins:


Zwitterionic compounds. Good affinity for the transpeptidase enzyme. Low affinity for some β-lactamases. Cross BBB and effective in meningitis.

4th Generation Cephalosporins:

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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


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 effectNephrotoxicityBleedingAllergic reactionsPhlebitis

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


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

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MONOBACTAMS


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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

47VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)

(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.VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 48

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


Conclusion:

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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.


Reference:

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Education

Prof. Dr. Ravisankar