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
Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
• 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
Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
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
Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
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
Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
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
Mechanism of action - bacterial cell wall synthesisMechanism of action - bacterial cell wall synthesis
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
Resistance to Resistance to PenicillinsPenicillins
Cell
Cell membrane
Thick porous cell wall
Gram + bacteriaGram + bacteria
• Thick cell wall• No outer membrane• More susceptible to penicillins
Resistance to Resistance to PenicillinsPenicillins
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
Resistance to Resistance to PenicillinsPenicillins
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
Problem 1 - Acid SensitivityProblem 1 - Acid Sensitivity
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
Problem 1 - Acid SensitivityProblem 1 - Acid Sensitivity
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)
Problem 1 - Acid SensitivityProblem 1 - Acid Sensitivity
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.
Problem 3 - Range of ActivityProblem 3 - Range of 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
Problem 3 - Range of ActivityProblem 3 - Range of Activity
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
Problem 3 - Range of ActivityProblem 3 - Range of Activity
• 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
5. First Generation 5. First Generation CephalosporinsCephalosporins
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
5. First Generation 5. First Generation CephalosporinsCephalosporins
SummarySummary
6. First Generation 6. First Generation CephalosporinsCephalosporins
• 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
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