Topic 8-1 Antibacterial Agents · SAR Conclusions • Amide and carboxylic acid are involved in...

Topic 8-1 Antibacterial Agents

β-Lactam antibiotics-Chapter 16Patrick

PENICILLINSPENICILLINS

N

S Me

Me

H

N

CO2H

O

C H H

O

R

INTRODUCTIONINTRODUCTION

• Antibacterial agents which inhibit bacterial cell wall synthesis• Discovered by Fleming from a fungal colony (1928)• Shown to be non toxic and antibacterial• Isolated and purified by Florey and Chain (1938)• First successful clinical trial (1941)• Produced by large scale fermentation (1944)• Structure established by X-Ray crystallography (1945)• Full synthesis developed by Sheehan (1957)• Isolation of 6-APA by Beechams (1958-60)

- development of semi-synthetic penicillins• Discovery of clavulanic acid and β-lactamase inhibitors

Acyl Acyl side side chainchain

6-Aminopenicillanic acid6-Aminopenicillanic acid(6-APA)(6-APA)

STRUCTURESTRUCTURE

Side chain varies depending on carboxylic acid present in fermentation medium

ββ-Lactam-Lactamringring

ThiazolidineThiazolidineringring

present in corn steep liquor

Penicillin GCH2 CO2H

Benzyl penicillin (Pen G)Benzyl penicillin (Pen G)

R =R =

PhenoxymethylPhenoxymethyl penicillin (Pen V) penicillin (Pen V)

R =R =

CH2

O CH2

N

S Me

Me

H

NH H

CO2H

O

C

O

R

Penicillin V(first orally active penicillin)

OCH2 CO2H

Shape of Penicillin GShape of Penicillin G

Folded Folded ‘‘envelopeenvelope’’ shape shape

HNO

NHC

O

R

H

S

CO2H

H

Me

Me

..

CYSCYS VALVAL

Biosynthesis of Biosynthesis of PenicillinsPenicillins

S

N

Me

MeO

H

N

CO2H

C

R

O

Properties of Penicillin GProperties of Penicillin G

• Active vs. Gram + bacilli and some Gram - cocci• Non toxic• Limited range of activity• Not orally active - must be injected• Sensitive to β-lactamases

(enzymes which hydrolyse the β-lactam ring)• Some patients are allergic• Inactive vs. Staphylococci

Drug DevelopmentDrug Development AimsAims• To increase chemical stability for oral administration• To increase resistance to β-lactamases• To increase the range of activity

SARSAR

ConclusionsConclusions• Amide and carboxylic acid are involved in binding• Carboxylic acid binds as the carboxylate ion• Mechanism of action involves the β-lactam ring• Activity related to β-lactam ring strain

(subject to stability factors)• Bicyclic system increases β-lactam ring strain• Not much variation in structure is possible• Variations are limited to the side chain (R)

Bicyclic system essential

N

S Me

Me

H

N

CO2H

O

C H H

O

R

Carboxylic acid essential

Cis Stereochemistry essential

!"Lactam essential

Amide essential

• Penicillins inhibit a bacterial enzyme called the transpeptidaseenzyme which is involved in the synthesis of the bacterial cell wall

• The β-lactam ring is involved in the mechanism of inhibition• Penicillin becomes covalently linked to the enzyme’s active site

leading to irreversible inhibition

Covalent bond formed Covalent bond formed to to transpeptidasetranspeptidase enzyme enzymeIrreversible inhibitionIrreversible inhibition

N

S Me

Me

HN H H

CO2HO

CO

RNu

Enz

C

H

N

C

CO2H

HH

Me

MeS

HN

O

R

O

Nu-Enz-H

N

S Me

Me

H

NH H

CO2H

O

C

H

Enz-Nu

O

R

Mechanism of actionMechanism of action

OH

Serz

L-Ala

D-Glu

L-Lys

L-Ala

D-Glu

L-LysL-Ala

D-Glu

L-Lys

L-Ala

D-Glu

L-Lys

L-Ala

D-Glu

L-Lys

L-Ala

D-Glu

L-LysL-Ala

D-Glu

L-Lys

L-Ala

D-Glu

L-Lys

L-Ala

D-Glu

L-Lys

Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis

NAM NAM NAMNAGNAG

NAM NAM NAMNAGNAG

NAM NAM NAMNAGNAG

Bond formationinhibited bypenicillin

D-Alanine

TRANSPEPTIDASE

PENICILLIN

SUGAR

BACKBONE

NAM

L-Ala

NAG

D-Glu

L-Lys

D-Ala

D-Ala

Gly Gly Gly Gly Gly Gly GlyGlyGlyGlyL-Lys

NAG

D-Ala

D-Ala

D-Glu

L-Ala

NAM

SUGAR

BACKBONE

L-Lys Gly Gly

D-Ala

NAM

L-Ala

NAG

D-Glu

L-Lys Gly Gly Gly Gly GlyGlyGlyGly

NAG

D-Ala

D-Glu

L-Ala

NAM

Cross linkingCross linking


• Penicillin inhibits final crosslinking stage of cell wall synthesis• It reacts with the transpeptidase enzyme to form an irreversible

covalent bond• Inhibition of transpeptidase leads to a weakened cell wall• Cells swell due to water entering the cell, then burst (lysis)• Penicillin possibly acts as an analogue of the L-Ala-γ-D-Glu

portion of the pentapeptide chain. However, the carboxylategroup that is essential to penicillin activity is not present in thisportion


Alternative theoryAlternative theory- - Pencillin Pencillin mimics D-Ala-D-Ala.mimics D-Ala-D-Ala.

Normal MechanismNormal Mechanism

Peptide

Chain

D-Ala D-Ala CO2H

OH

Peptide

Chain

Gly

HOH

Peptide

Chain

Peptide

Chain

D-Ala GlyPeptide

Chain

O

D-Ala


Alternative theoryAlternative theory- - Pencillin Pencillin mimics D-Ala-D-Ala.mimics D-Ala-D-Ala.

Mechanism inhibited by penicillinMechanism inhibited by penicillin

OH

Peptide

Chain

Gly

H

BlockedH2O

Blocked

Blocked Irreversibly blocked

HCR

O

CO2H

NH

OMe

Me

N

S

S

HN

O

O

Me

Me

NH

CO2H

C

O

R HS

HN

O

O

Me

Me

NH

CO2H

C

O

R H


Penicillin can be seen to mimic Penicillin can be seen to mimic acyl-D-Ala-D-Alaacyl-D-Ala-D-Ala

PenicillinPenicillin Acyl-D-Ala-D-AlaAcyl-D-Ala-D-Ala

HH

CO2H

H

N

OMe

Me

N

SC

R

O

Me

CO2H

H

N

OCH3

H

N

H

H

C

R

O


Resistance to Resistance to PenicillinsPenicillins

• Penicillins have to cross the bacterial cell wall in order to reachtheir target enzyme

• But cell walls are porous and are not a barrier

• The cell walls of Gram + bacteria are thicker than Gram - cellwalls, but the former are more susceptible to penicillins


Cell

Cell membrane

Thick porous cell wall

Gram + bacteriaGram + bacteria

• Thick cell wall• No outer membrane• More susceptible to penicillins


L

CellCellmembrane

Thin cell wall

Lactamaseenzymes

Outer membrane

Hydrophobic barrier

Periplasmicspace

Porin

LL

L

Gram - bacteriaGram - bacteria

• Thin cell wall• Hydrophobic outer membrane• More resistant to penicillins


FactorsFactors• Gram - bacteria have a lipopolysaccharide outer membrane

preventing access to the cell wall• Penicillins can only cross via porins in the outer membrane• Porins only allow small hydrophilic molecules that can exist as

zwitterions to cross• High levels of transpeptidase enzyme may be present• The transpeptidase enzyme may have a low affinity for

penicillins• Presence of β-lactamases• Concentration of β-lactamases in periplasmic space• Transfer of β-lactamases between strains• Efflux mechanisms pumping penicillin out of periplasmic space

Penicillin Analogues - PreparationPenicillin Analogues - Preparation

1) By fermentation1) By fermentation• vary the carboxylic acid in the fermentation medium• limited to unbranched acids at the α-position i.e. RCH2CO2H• tedious and slow

2) By total synthesis2) By total synthesis • only 1% overall yield (impractical)

3) By semi-synthetic procedures3) By semi-synthetic procedures•• Use a naturally occurring structure as the starting material forUse a naturally occurring structure as the starting material for

analogue synthesisanalogue synthesis

Penicillin Analogues - PreparationPenicillin Analogues - Preparation

Fermentation

Penicillin Penicillin acylaseacylaseor chemical hydrolysisor chemical hydrolysis

O

CClR

Penicillin G

HC

H

N

CO2H

OMe

Me

N

S

O

CH2

6-APA

O

CO2H

HHH2N

Me

MeS

N

Semi-synthetic Semi-synthetic penicillinspenicillinsN

S Me

Me

H

NH H

CO2H

O

C

O

R

Problems with Penicillin GProblems with Penicillin G

• It is sensitive to stomach acids• It is sensitive to β-lactamases - enzymes which hydrolyse the β-

lactam ring• it has a limited range of activity

Penicillin G

HC

H

N

CO2H

OMe

Me

N

S

O

CH2

Problem 1 - Acid SensitivityProblem 1 - Acid Sensitivity Reasons for sensitivityReasons for sensitivity

Factor Factor 1) Ring Strain1) Ring Strain

H2O

H

N

S Me

Me

H

N

H H

CO2H

O

C

O

R

Relieves ring strainRelieves ring strain

C

H

N

HO2C

CO2H

HH

Me

MeS

HN

O

R

Acid or enzyme

N

S Me

Me

H

N

H H

CO2H

O

C

HO

O

R

Problem 1 - Acid SensitivityProblem 1 - Acid Sensitivity

Factor Factor 2) Reactive 2) Reactive ββ-lactam -lactam carbonyl groupcarbonyl group Does not behave like a tertiary amideDoes not behave like a tertiary amide

• Interaction of nitrogen’s lone pair with the carbonyl group is not possible • Results in a reactive carbonyl group

Tertiary amideTertiary amide

C

O

R

NR2Unreactive

R

C

R

N

O

R

ββ-Lactam-Lactam

Folded ringsystem

N

S

OH

Me

Me

CO2H

Impossiblystrained

N

S

Me

Me

CO2H

O

Reasons for sensitivityReasons for sensitivity

X


Factor 3) Factor 3) Acyl Acyl Side ChainSide Chain - - neighbouring group participation in the hydrolysis mechanism

H

Furtherreactions

-H

N

S

O

N

O

R R

O

N

O

S

HN

C N

O

S

N

H

R

O

H

Reasons for sensitivityReasons for sensitivity

C

E.W.G.

O

H

N

O

S

N

H


ConclusionsConclusions• The β-lactam ring is essential for activity and must be retained• Therefore, cannot tackle factors 1 and 2• Can only tackle factor 3

StrategyStrategyVary the acyl side group (R) to make it electron withdrawing todecrease the nucleophilicity of the carbonyl oxygen

DecreasesDecreasesnucleophilicitynucleophilicity

N

S

H

N

O

C

O

CH2PhOH

Penicillin VPenicillin V(orally active)(orally active)


ExamplesExamples

electronegativeelectronegativeoxygenoxygen

• Very successful semi-synthetic penicillinse.g. ampicillin, oxacillin

• Better acid stability and orally active• But sensitive to β-lactamases• Slightly less active than Penicillin G• Allergy problems with some patients

X = NH2, Cl, PhOCONH, Heterocycles, CO2H

C

HC

O

H

N

O

S

N

X

R

H!

Problem 2 - Sensitivity to Problem 2 - Sensitivity to b-Lactamasesb-Lactamases Notes on Notes on ββ-Lactamases-Lactamases• Enzymes that inactivate penicillins by opening β-lactam rings• Allow bacteria to be resistant to penicillin• Transferable between bacterial strains (i.e. bacteria can acquire

resistance)• Important to Staphylococcus aureus infections in hospitals• 80% Staph. infections in hospitals were resistant to penicillin and

other antibacterial agents by 1960!• Mechanism of action for lactamases is identical to the mechanism

of inhibition for the target enzyme• But product is removed efficiently from the lactamase active site

β-LactamaseN

S Me

Me

H

N

CO2H

O

CH

O

R

C

H

N

CO2H

Me

MeS

HN

H

HO2C

O

R

BulkyBulkygroupgroup

Problem 2 - Sensitivity to Problem 2 - Sensitivity to b-Lactamasesb-Lactamases

StrategyStrategy

EnzymeEnzyme

C

R

H

N

O

CO2H

Me

MeS

N

H H

O

• Block access of penicillin to active site of enzyme by introducingbulky groups to the side chain to act as steric shields

• Size of shield is crucial to inhibit reaction of penicillins with β-lactamases but not with the target enzyme (transpeptidase)

orthoortho groupsgroupsimportantimportant

Problem 2 - Sensitivity to Problem 2 - Sensitivity to b-Lactamasesb-Lactamases ExamplesExamples - Methicillin ( - Methicillin (BeechamsBeechams - 1960) - 1960)

• Methoxy groups block access to β-lactamases but not to transpeptidases• Active against some penicillin G resistant strains (e.g. Staphylococcus)• Acid sensitive (no e-withdrawing group) and must be injected• Lower activity w.r.t. Pen G vs. Pen G sensitive bacteria (reduced access

to transpeptidase)• Poorer range of activity• Poor activity vs. some streptococci• Inactive vs. Gram - bacteria

N

S Me

Me

H

N

CO2H

O

MeO

OMe

H HC

O

Problem 2 - Sensitivity to Problem 2 - Sensitivity to ββ-Lactamases-Lactamases ExamplesExamples - Oxacillin - Oxacillin

• Orally active and acid resistant• Resistant to β-lactamases• Active vs. Staphylococcus aureus• Less active than other penicillins• Inactive vs. Gram -ve bacteria• Nature of R & R’ influences absorption and plasma protein binding• Cloxacillin better absorbed than oxacillin• Flucloxacillin less bound to plasma protein, leading to higher

levels of free drug

Bulky and e- withdrawing

Oxacillin R = R' = HOxacillin R = R' = HCloxacillinCloxacillin R = Cl, R' = H R = Cl, R' = HFlucloxacillinFlucloxacillin R = Cl, R' = F R = Cl, R' = F

N

O

C

O

H

N

O

CO2H

Me

MeS

N

R'

R

Me

H H

Problem 3 - Range of ActivityProblem 3 - Range of Activity

FactorsFactors1. Cell wall may have a coat preventing access to the cell2. Excess transpeptidase enzyme may be present3. Resistant transpeptidase enzyme (modified structure)4. Presence of β-lactamases5. Transfer of β-lactamases between strains6. Efflux mechanisms

StrategyStrategy• The number of factors involved make a single strategy

impossible• Use trial and error by varying R groups on the side chain• Successful in producing broad spectrum antibiotics• Results demonstrate general rules for broad spectrum activity.


1. R= hydrophobic results in high activity vs. Gram + bacteria andpoor activity vs. Gram -ve bacteria

2. Increasing hydrophobicity has little effect on Gram + activity butlowers Gram -ve activity

3. Increasing hydrophilic character has little effect on Gram+ activity but increases Gram - activity

4. Hydrophilic groups at the α-position (e.g. NH2, OH, CO2H)increase activity vs Gram - bacteria

Results of varying R in Pen GResults of varying R in Pen G


Examples of Broad Spectrum Examples of Broad Spectrum PenicillinsPenicillins

Class 1 - NHClass 1 - NH22 at the at the αα-position-position Ampicillin and Amoxycillin (Ampicillin and Amoxycillin (BeechamsBeechams, 1964), 1964)

Ampicillin (Ampicillin (PenbritinPenbritin))2nd most used penicillin2nd most used penicillin

Amoxycillin (Amoxycillin (AmoxilAmoxil))

H

C

H

O

H

NC

NH2

HO

O

C

NH2

C

H

N

O

H

H

O


• Active vs Gram + bacteria and Gram - bacteria which do notproduce β-lactamases

• Acid resistant and orally active• Non toxic• Still sensitive to β-lactamases• Increased polarity due to extra amino group• Poor absorption through the gut wall• Disruption of gut flora leading to diarrhea• Inactive vs. Pseudomonas aeruginosa

Examples of Broad Spectrum PenicillinsExamples of Broad Spectrum Penicillins

PropertiesProperties

O

N

H

NC

C

NH2

SMe

Me

CO2R

H H

H

O

Problem 3 - Range of ActivityProblem 3 - Range of Activity Prodrugs Prodrugs of of AmpicillinAmpicillin (Leo Pharmaceuticals - 1969)(Leo Pharmaceuticals - 1969)

PropertiesProperties• Increased cell membrane permeability• Polar carboxylic acid group is masked by the ester• Ester is metabolised in the body by esterases to give the free

drug

PIVAMPICILLINR = CH2O

C

O

CMe3

TALAMPICILLINR = O

O

BACAMPICILLIN

R = CH

Me

OC

O

O CH2Me

Problem 3 - Range of ActivityProblem 3 - Range of Activity Examples of Broad Spectrum Examples of Broad Spectrum PenicillinsPenicillinsClass 2 - COClass 2 - CO22H at the H at the αα-position (-position (carboxypenicillinscarboxypenicillins))

ExamplesExamples

• Carfecillin = prodrug for carbenicillin• Active over a wider range of Gram -ve bacteria than ampicillin• Active vs. Pseudomonas aeruginosa• Resistant to most β-lactamases• Less active vs Gram + bacteria (note the hydrophilic group)• Acid sensitive and must be injected• Stereochemistry at the α-position is important• CO2H at the α-position is ionized at blood pH

R = H CARBENICILLINR = H CARBENICILLINR = Ph CARFECILLINR = Ph CARFECILLINH H

O

N

H

NC

CH

CO2R

SMe

Me

CO2H

O

CEPHALOSPORINSCEPHALOSPORINS

N

S

OAc

CO2H

O

HN H HC

O

R

1. Introduction1. Introduction

• Antibacterial agents which inhibit bacterial cell wall synthesis

• Discovered from a fungal colony in Sardinian sewer water (1948)

• Cephalosporin C identified in 1961

N

O

HHHN

O

S

CO2H

OC

Me

O

H2N

CO2H

7H

61

2

34

58

7-Aminoadipic side chain7-Aminoadipic side chain

2. Structure of Cephalosporin C2. Structure of Cephalosporin C

ββ-Lactam-Lactamringring

DihydrothiazineDihydrothiazineringring

N

O

HH

H2NS

CO2H

OC

Me

O

7-Aminocephalosporinic acid (7-ACA)7-Aminocephalosporinic acid (7-ACA)

N

O

HHHN

O

S

CO2H

OC

Me

O

H2N

CO2H

7H

61

2

34

583. Properties of Cephalosporin C3. Properties of Cephalosporin C

DisadvantagesDisadvantages• Polar due to the side chain - difficult to isolate and purify• Low potency - limited to the treatment of urinary tract infections

where it is concentrated in the urine• Not absorbed orallyAdvantagesAdvantages• Non toxic• Lower risk of allergic reactions compared to penicillins• More stable to acid conditions• More stable to β-lactamases• Ratio of activity vs Gram - and Gram + bacteria is better

ConclusionConclusion • Useful as a lead compound

4. SAR of 4. SAR of CephalosporinsCephalosporins

Similar to Similar to penicillinspenicillins• The β-lactam ring is crucial to the mechanism• The carboxylic acid at position 4 is important to binding• The bicyclic system is important in increasing ring strain• Stereochemistry is important• The acetoxy substituent is important to the mechanism

Possible modificationsPossible modifications• 7-Acylamino side chain• 3-Acetoxymethyl side chain• Substitution at C-7

N

O

HHHNR

O

S

CO2H

OC

Me

O

7 61

2

34

58

5. First Generation 5. First Generation CephalosporinsCephalosporinsCephalothinCephalothin

N

O

HHHN S

CO2H

OAcOS

7

3

• First generation cephalosporin• More active than penicillin G vs. some Gram - bacteria• Less likely to cause allergic reactions• Useful vs. penicillinase producing strains of S. aureus• Not active vs. Pseudonomas aeruginosa• Poorly absorbed from gut• Administered by injection• Metabolised to give a free 3-hydroxymethyl group (deacetylation)• Metabolite is less active

Cephalothin Cephalothin - drug metabolism- drug metabolism

StrategyStrategy•• Replace the Replace the acetoxy acetoxy group with a metabolically stable leavinggroup with a metabolically stable leaving

groupgroup

N

O

HHHN S

CO2H

OAcOS

7

3

MetabolismMetabolismN

O

HHHN S

CO2H

OHOS

Less activeLess activeOH is a poorer leaving groupOH is a poorer leaving group

5. First Generation 5. First Generation CephalosporinsCephalosporins

CephaloridineCephaloridine

• The pyridine ring is stable to metabolism

• The pyridine ring is a good leaving group (neutralisation ofcharge)

• Exists as a zwitterion and is soluble in water

• Poorly absorbed through the gut wall

• Administered by injection

N

O

HHHN S

CO2

NOS

7

3


CefalexinCefalexin

• The methyl group at position 3 is not a good leaving group

• The methyl group is bad for activity but aids oral absorption -mechanism unknown

• Cefalexin can be administered orally• A hydrophilic amino group at the α-carbon of the side chain helps

to compensate for the loss of activity due to the methyl group

N

O

HHHN S

CO2H

Me

O

H2N H

7

3


SummarySummary


• Generally lower activity than comparable penicillins• Better range of activity than comparable penicillins• Best activity is against Gram-positive cocci• Useful against some Gram negative infections• Useful against S. aureus and streptococcal infections when

penicillins have to be avoided• Poorly absorbed across the gut wall (except for 3-methyl

substituted cephalosporins)• Most are administered by injection• Resistance has appeared amongst Gram negative bacteria

(presence of more effective β-lactamases))

CephamycinsCephamycins

6. Second Generation 6. Second Generation CephalosporinsCephalosporins

• Isolated from a culture of Streptomyces clavuligerus• First β-lactam to be isolated from a bacterial source

• Modifications carried out on the 7-acylamino side chain

N

O

HOMeHN S

CO2H

OO

C

NH2

O

HO2C

H2N H Cephamycin CCephamycin C

CefoxitinCefoxitin

• Broader spectrum of activity than most first generationcephalosporins

• Greater resistance to β-lactamase enzymes• The 7-methoxy group may act as a steric shield• The urethane group is stable to metabolism compared to the ester• Introducing a methoxy group to the equivalent position of

penicillins (position 6) eliminates activity.

N

O

HOMeHN S

CO2H

OO

C

NH2

O

S

7

3

6 6 CephamycinsCephamycins

6. Second Generation 6. Second Generation CephalosporinsCephalosporins

CefuroximeCefuroxime

• Much greater stability against some β-lactamases• Resistant to esterases due to the urethane group• Wide spectrum of activity• Useful against organisms that have gained resistance to penicillin• Not active against P. aeruginosa• Used clinically against respiratory infections

6. Second Generation 6. Second Generation CephalosporinsCephalosporinsOximinocephalosporinsOximinocephalosporins

N

O

HHHN S

CO2H

O

C

O

C

NH2

O

O

N

O

Me

Newer Newer ββ-Lactam -Lactam AntibioticsAntibiotics ThienamycinThienamycin (Merck 1976)(from (Merck 1976)(from StreptomycesStreptomyces cattleya) cattleya)

• Potent and wide range of activity vs Gram + and Gram - bacteria• Active vs. Pseudomonas aeruginosa• Low toxicity• High resistance to β-lactamases• Poor stability in solution (ten times less stable than Pen G)

Oppositestereochemistry to penicillins

Carbon

Carbapenam nucleus

Plays a rolein ß-lactamaseresistance

Acylamino sidechain absent

O

N

S

OH

H3C

CO2

H

NH3

H

Double bond leading to high ring strain and an increasein !-lactam ring reactivity

Newer Newer ββ-Lactam -Lactam AntibioticsAntibiotics Clinically useful Clinically useful monobactammonobactam

• Administered by intravenous injection• Can be used for patients with allergies to penicillins

and cephalosporins• No activity vs. Gram + or anaerobic bacteria• Active vs. Gram - aerobic bacteria

AztreonamAztreonamN

O

HN

O

SO3-

Me

NO

CO2HMeMe

N

S

H2N

ββ-Lactamase -Lactamase InhibitorsInhibitors

ClavulanicClavulanic acid acid ( (BeechamsBeechams 1976)(from 1976)(from StreptomycesStreptomyces clavuligerusclavuligerus))

• Weak, unimportant antibacterial activity• Powerful irreversible inhibitor of β-lactamases - suicide substrate• Used as a sentry drug for ampicillin • Augmentin = ampicillin + clavulanic acid• Allows less ampicillin per dose and an increased activity spectrum• Timentin = ticarcillin + clavulanic acid

No acylaminoside chain

Sulphur replaced by O

Oxazolidine ring

!-Lactam

9

2

5

3

4

17

6

H

CO2H

O

N

OH

OH

H

Penicillanic Penicillanic acid acid sulfone sulfone derivativesderivatives

• Suicide substrates for β-lactamase enzymes• Sulbactam has a broader spectrum of activity vs β-lactamases than

clavulanic acid, but is less potent• Unasyn = ampicillin + sulbactam• Tazobactam has a broader spectrum of activity vs β-lactamases than

clavulanic acid, and has similar potency• Tazocin or Zosyn = piperacillin + tazobactam

ββ-Lactamase -Lactamase InhibitorsInhibitors

N

O

S

CO2

OO

Me

Me

Na

N

O

S

CO2

OO

Me

N

NN

1

2

3

56

7

6

3

SulbactamSulbactam TazobactamTazobactam

Topic 8-1 Antibacterial Agents · SAR Conclusions • Amide and carboxylic acid are involved in...

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