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Antibiotics

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Antibiotics
Antibiotics
Step 1: How to Kill a Bacterium.
• What are the bacterial weak points?
• Specifically, which commercial antibiotics
target each of these points?
Target 1: The Bacterial Cell
Envelope
Structure of the bacterial cell envelope. Gram-positive. Gram-negative.
Structure of peptidoglycan. Peptidoglycan synthesis requires cross-linking of
disaccharide polymers by penicillin-binding proteins (PBPs). NAMA, N-acetylmuramic acid; NAGA, N-acetyl-glucosamine.
Antibiotics that Target the Bacterial
Cell Envelope Include:
• The b-Lactam Antibiotics
• Vancomycin
• Daptomycin
Target 2: The Bacterial Process of
Protein Production
An overview of the process by which proteins are produced within bacteria.
Structure of the bacterial ribosome.
Antibiotics that Block Bacterial
Protein Production Include:
•
•
•
•
•
•
•
•
Rifamycins
Aminoglycosides
Macrolides and Ketolides
Tetracyclines and Glycylcyclines
Chloramphenicol
Clindamycin
Streptogramins
Linezolid (member of Oxazolidinone Class)
Target 3: DNA and Bacterial
Replication
Bacterial synthesis of tetrahydrofolate.
Supercoiling of the double helical structure of DNA. Twisting of DNA results in
formation of supercoils. During transcription, the movement of RNA polymerase
along the chromosome results in the accumulation of positive supercoils ahead
of the enzyme and negative supercoils behind it. (Adapted with permission from
Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. New York:
Garland Science, 2002:314.)
Replication of the bacterial chromosome. A consequence of the circular nature of
the bacterial chromosome is that replicated chromosomes are interlinked,
requiring topoisomerase for appropriate segregation.
Antibiotics that Target DNA and
Replication Include:
• Sulfa Drugs
• Quinolones
• Metronidazole
Which Bacteria are Clinically
Important?
General Classes of Clinically
Important Bacteria Include:
•
•
•
•
•
•
Gram-positive aerobic bacteria
Gram-negative aerobic bacteria
Anaerobic bacteria (both Gram + and -)
Atypical bacteria
Spirochetes
Mycobacteria
Gram-positive Bacteria of
Clinical Importance
• Staphylococci
– Staphylococcus aureus
– Staphylococcus epidermidis
• Streptococci
–
–
–
–
Streptococcus pneumoniae
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus viridans
• Enterococci
– Enterococcus faecalis
– Enterococcus faecium
• Listeria monocytogenes
• Bacillus anthracis
Gram-negative Bacteria of
Clinical Importance
• Enterobacteriaceae
– Escherichia coli, Enterobacter, Klebsiella, Proteus, Salmonella,
Shigella, Yersinia, etc.
• Pseudomonas aeruginosa
• Neisseria
– Neisseria meningitidis and Neisseria gonorrhoeae
• Curved Gram-negative Bacilli
– Campylobacter jejuni, Helicobacter pylori, and Vibrio cholerae
•
•
•
•
Haemophilus Influenzae
Bordetella Pertussis
Moraxella Catarrhalis
Acinetobacter baumannii
Anaerobic Bacteria of Clinical
Importance
• Gram-positive anaerobic bacilli
– Clostridium difficile
– Clostridium tetani
– Clostridium botulinum
• Gram-negative anaerobic bacilli
– Bacteroides fragilis
Atypical Bacteria of Clinical
Importance Include:
•
•
•
•
•
•
Chlamydia
Mycoplasma
Legionella
Brucella
Francisella tularensis
Rickettsia
Spirochetes of Clinical
Importance Include:
• Treponema pallidum
• Borrelia burgdorferi
• Leptospira interrogans
Mycobacteria of Clinical
Importance Include:
• Mycobacterium tuberculosis
• Mycobacterium avium
• Mycobacterium leprae
Antibiotics that Target the Bacterial
Cell Envelope
• The b-Lactam Antibiotics
Mechanism of action of β-lactam antibiotics. Normally, a new subunit of Nacetylmuramic acid (NAMA) and N-acetylglucosamine (NAGA) disaccharide with an
attached peptide side chain is linked to an existing peptidoglycan polymer. This may
occur by covalent attachment of a glycine () bridge from one peptide side chain to
another through the enzymatic action of a penicillin-binding protein (PBP). In the
presence of a β-lactam antibiotic, this process is disrupted. The β-lactam antibiotic
binds the PBP and prevents it from cross-linking the glycine bridge to the peptide
side chain, thus blocking incorporation of the disaccharide subunit into the existing
peptidoglycan polymer.
Mechanism of penicillin-binding protein (PBP) inhibition by β-lactam antibiotics.
PBPs recognize and catalyze the peptide bond between two alanine subunits of
the peptidoglycan peptide side chain. The β-lactam ring mimics this peptide
bond. Thus, the PBPs attempt to catalyze the β-lactam ring, resulting in
inactivation of the PBPs.
Six P's by which the
action of βlactams may be
blocked:
(1) penetration,
(2) porins,
(3) pumps,
(4) penicillinases (βlactamases),
(5) penicillin-binding
proteins (PBPs),
and
(6) peptidoglycan.
The Penicillins
Category
Parenteral Agents
Oral Agents
Natural Penicillins
Penicillin G
Penicillin V
Antistaphylococcal
penicillins
Nafcillin, oxacillin
Dicloxacillin
Aminopenicillins
Ampicillin
Amoxicillin and Ampicillin
Aminopenicillin + blactamase inhibitor
Ampicillin-sulbactam
Amoxicillin-clavulanate
Extended-spectrum
penicillin
Piperacillin, ticaricillin
Carbenicillin
Extended-spectrum
penicillin + b-lactamase
inhibitor
Piperacillin-tazobactam,
ticaricillin-clavulanate
INTRODUCTION
•
•
•
•
•
•
•
•
•
•
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 b-lactamase inhibitors
http://www.microbelibrary.org/microbelibrary/files/ccImages/Articl
eimages/Spencer/spencer_cellwall.html
STRUCTURE
R=
O
CH2
C
Benzyl penicillin (Pen G)
H
S
Me
6-Aminopenicillanic acid
(6-APA)
R
R=
O
H H
N
Acyl side
chain
CH2
N
Me
O
CO2H
b-Lactam
ring
Phenoxymethyl penicillin (Pen V)
Thiazolidine
ring
Side chain varies depending on carboxylic acid present in fermentation medium
CH2
CO2H
Penicillin G
present in corn steep liquor
OCH2
CO2H
Penicillin V
(first orally active penicillin)
Shape of Penicillin G
O
C
R
Me
H
NH
S
Me
O
H
N
H
CO2H
..
Folded ‘envelope’ shape
Properties of Penicillin G
•
•
•
•
•
•
•
Active vs. Gram +ve bacilli and some Gram -ve cocci
Non toxic
Limited range of activity
Not orally active - must be injected
Sensitive to b-lactamases
(enzymes which hydrolyse the b-lactam ring)
Some patients are allergic
Inactive vs. Staphylococci
Drug Development
Aims
• To increase chemical stability for oral administration
• To increase resistance to b-lactamases
• To increase the range of activity
SAR
Amide essential
O
C
H
N
Cis Stereochemistry essential
H
H
S
R
Me
N
O
b Lactam essential CO2H
Conclusions
•
•
•
•
•
•
•
Me
Carboxylic acid essential
Bicyclic system ess ential
Amide and carboxylic acid are involved in binding
Carboxylic acid binds as the carboxylate ion
Mechanism of action involves the b-lactam ring
Activity related to b-lactam ring strain
(subject to stability factors)
Bicyclic system increases b-lactam ring strain
Not much variation in structure is possible
Variations are limited to the side chain (R)
Mechanism of action
•
Penicillins inhibit a bacterial enzyme called the transpeptidase
enzyme which is involved in the synthesis of the bacterial cell
wall
The b-lactam ring is involved in the mechanism of inhibition
Penicillin becomes covalently linked to the enzyme’s active site
leading to irreversible inhibition
•
•
O
C
H H
N
S
R
N
Nu
O
H
Me
Me
O
Enz
C
CO2H
H H
N
R
Enz-Nu
-H
O
H
S
N
Me
Me
O
H
CO2H
C
H H
N
H
R
O C HN
Nu-Enz
S
Me
Me
CO2H
Covalent bond formed
to transpeptidase enzyme
Irreversible inhibition
Mechanism of action - bacterial cell wall synthesis
NAM
L-Ala
D-Glu
L-Lys
NAG
NAM
L-Ala
D-Glu
L-Lys
Bond formation
inhibited by
penicillin
NAM
L-Ala
NAG
D-Glu
NAM
L-Lys
L-Ala
NAG
NAM
L-Ala
NAG
D-Glu
L-Lys
NAM
L-Ala
NAG
NAM
D-Glu
L-Ala
NAM
NAG
L-Lys
NAM
D-Glu
L-Ala
L-Lys
L-Ala
D-Glu
D-Glu
D-Glu
L-Lys
L-Lys
L-Lys
Mechanism of action - bacterial cell wall synthesis
NAM
NAG
NAM
L-Ala
L-Ala
D-Glu
D-Glu
L-Lys
Gly Gly Gly Gly Gly
NAG
L-Lys
D-Ala
D-Ala
D-Ala
D-Ala
SUGAR
BACKBONE
Gly Gly Gly Gly Gly
PENICILLIN
D-Alanine
NAM
NAG
TRANSPEPTIDASE
NAM
L-Ala
L-Ala
D-Glu
D-Glu
L-Lys
D-Ala
Gly Gly Gly Gly Gly
Cross linking
L-Lys
D-Ala
NAG
Gly Gly Gly Gly Gly
SUGAR
BACKBONE
Mechanism 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-g-D-Glu
portion of the pentapeptide chain. However, the carboxylate
group that is essential to penicillin activity is not present in
this portion
Mechanism of action - bacterial cell wall synthesis
Alternative theory- Pencillin mimics D-Ala-D-Ala.
Normal Mechanism
Pe ptide
Chain
D-Ala
OH
Pe ptide
Chain
Pe ptide
Chain
D-Ala
CO 2H
Pe ptide
Chain
D-Ala
Gly
D-Ala
O
H
OH
Pe ptide
Chain
Gly
Mechanism of action - bacterial cell wall synthesis
Alternative theory- Penicillin mimics D-Ala-D-Ala.
Mechanism inhibited by penicillin
Blocked
Pe ptide
Chain
Blocked
H2O
O
R
C
O
H
NH
S
N
O
H
OH
Me
Me
R
O
Gly
C
NH
H
O
R
S
NH
H
O
HN
HN
Me
CO2H
O
C
Me
CO2H
Blocked
O
S
Me
Me
CO2H
Irreversibly blocked
Mechanism of action - bacterial cell wall synthesis
Penicillin can be seen to mimic acyl-D-Ala-D-Ala
R
R
C
H
N
H
H
S
C
Me
O
H
N
H
H
N
O
N
O
Me
O
CO2H
Penicillin
Me
H
CH3
CO2H
Acyl-D-Ala-D-Ala
Penicillin Analogues - Preparation
1) By fermentation
• vary the carboxylic acid in the fermentation medium
• limited to unbranched acids at the a-position i.e. RCH2CO2H
• tedious and slow
2) By total synthesis
• only 1% overall yield (impractical)
3) By semi-synthetic procedures
• Use a naturally occurring structure as the starting material for
analogue synthesis
Penicillin Analogues - Preparation
O
H
N
C
H
S
CH2
Me
Penicillin G
N
Me
O
CO2H
Penicillin acylase
or chemical hydrolysis
H2N
Fermentation
H
H
S
N
Me
Me
O
6-APA
CO2H
O
R
C
Cl
O
C
H H
N
H
S
Me
R
N
Semi-synthetic penicillins
Me
O
CO2H
Penicillin Analogues - Preparation
Problem - How does one hydrolyse the side chain by chemical
means in presence of a labile b-lactam ring?
Answer - Activate the side chain first to make it more reactive
PhCH2
O
C NH
S
ROH
PhCH2 C N
PEN
N
O
PCl5
OR
Cl
H2O
PhCH2 C N
PEN
6-APA
CO2H
Note - Reaction with PCl5 requires involvement of nitrogen’s
lone pair of electrons. Not possible for the b-lactam nitrogen.
Problems with Penicillin G
•
It is sensitive to stomach acids
•
It is sensitive to b-lactamases - enzymes which hydrolyse the
b-lactam ring
•
it has a limited range of activity
Problem 1 - Acid Sensitivity
Reasons for sensitivity
1) Ring Strain
O
C
H
N
H
H
S
R
Me
Acid or
enzyme
O
O
C
H
N
N
Me
O
CO2H
H
S
R
HO
H2O
H
N
Me
Me
C
H
N
H
H
S
R
HO2C
HN
Me
Me
O
H
CO2H
CO2H
Relieves ring strain
Problem 1 - Acid Sensitivity
Reasons for sensitivity
2) Reactive b-lactam carbonyl group
Does not behave like a tertiary amide
Tertiary amide
R
R
C
R
C
NR2
O
O
b-Lactam
Unreactive
N
R
Me
S
S
Me
Me
O
N
CO2H
H
Folded ring
system
•
•
X
N
Me
O
CO2H
Impossibly
strained
Interaction of nitrogen’s lone pair with the carbonyl group is not possible
Results in a reactive carbonyl group
Problem 1 - Acid Sensitivity
Reasons for sensitivity
3) Acyl Side Chain
- neighbouring group participation in the hydrolysis mechanism
R
H
C
N
H
S
O
N
O
N
R
S
N
R
S
-H
O
N
O
O
HN
O
H
Further
reactions
Problem 1 - Acid Sensitivity
Conclusions
•
•
•
The b-lactam ring is essential for activity and must be retained
Therefore, cannot tackle factors 1 and 2
Can only tackle factor 3
Strategy
Vary the acyl side group (R) to make it electron withdrawing to
decrease the nucleophilicity of the carbonyl oxygen
H
N
E.W.G.
H
S
C
N
O
Decreases
nucleophilicity
O
Problem 1 - Acid Sensitivity
Examples
PhO
X
H
N
CH2
H
S
C
electronegative
oxygen
•
•
•
•
HC
N
Better acid stability and orally active
But sensitive to b-lactamases
Slightly less active than Penicillin G
Allergy problems with some patients
H
S
N
O
O
Penicillin V
(orally active)
H
N
C
R
O
a
O
X = NH 2, Cl, PhOCONH,
Heterocycles, CO2H
•
Very successful semisynthetic penicillins
e.g. ampicillin, oxacillin
Natural penicillins include Penicillin G (parenteral) and Penicillin V (oral)
Gram-positive
bacteria
Streptococcus pyogenes, Viridans group
streptococci, Some Streptococcus
pneumoniae, Some Enterococci, Listeria
monocytogenes
Gram-negative
bacterai
Neisseria meningitidis, Some Haemophilus
influenzae
Anaerobic
bacteria
Clostridia spp. (except C. difficile),
Antinomyces israelii
Spirochetes
Treponema pallidum Leptospira spp.
Problem 2 - Sensitivity to b-Lactamases
Notes on b-Lactamases
• Enzymes that inactivate penicillins by opening b-lactam rings
• Allow bacteria to be resistant to penicillin
• Transferable between bacterial strains (i.e. bacteria can
acquire resistance)
• Important w.r.t. 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
O
O
C
H
N
H
C
S
R
N
O
CO2H
H
S
Me
Me
H
N
R
b-Lactamase
HO2C
HN
Me
Me
CO2H
Problem 2 - Sensitivity to b-Lactamases
Strategy
• Block access of penicillin to active site of enzyme by
introducing bulky groups to the side chain to act as steric
shields
• Size of shield is crucial to inhibit reaction of penicillins with blactamases but not with the target enzyme (transpeptidase)
O
Bulky
group
C
H
N
H
H
S
Me
R
N
Enzyme
Me
O
CO2H
Problem 2 - Sensitivity to b-Lactamases
Examples - Methicillin (Beechams - 1960)
ortho groups
important
O
MeO
C
H
N
H
H
S
N
OMe
Me
Me
O
CO2H
•
•
•
•
•
•
•
Methoxy groups block access to b-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 -ve bacteria
Problem 2 - Sensitivity to b-Lactamases
Examples - Oxacillin
R'
O
C
R
N
O
H
H
S
N
Me
Bulky and
e- withdrawing
•
•
•
•
•
•
•
•
H
N
Me
Oxacillin
R = R' = H
Cloxacillin R = Cl, R' = H
Flucloxacillin R = Cl, R' = F
Me
O
CO2H
Orally active and acid resistant
Resistant to b-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
Antistaphylococcal Penicillins include Nafcillin and Oxacillin (parenteral) as well as
Dicloxacillin (oral)
Gram-positive bacteria
Some Staphylococcus
aureus, Some
Staphylococcus
epidermidis
Problem 3 - Range of Activity
Factors
1. Cell wall may have a coat preventing access to the cell
2. Excess transpeptidase enzyme may be present
3. Resistant transpeptidase enzyme (modified structure)
4. Presence of b-lactamases
5. Transfer of b-lactamases between strains
6. Efflux mechanisms
Strategy
• 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 Activity
Results of varying R in Pen G
1. R= hydrophobic results in high activity vs. Gram +ve bacteria
and poor activity vs. Gram -ve bacteria
2. Increasing hydrophobicity has little effect on Gram +ve activity
but lowers Gram -ve activity
3. Increasing hydrophilic character has little effect on Gram
+ve activity but increases Gram -ve activity
4. Hydrophilic groups at the a-position (e.g. NH2, OH, CO2H)
increase activity vs Gram -ve bacteria
Problem 3 - Range of Activity
Examples of Aminopenicillins include:
Class 1 - NH2 at the a-position
Ampicillin and Amoxycillin (Beecham, 1964)
H
H
NH2
HO
C
C
H
N
NH2
C
C
H
H
N
H
O
O
O
Ampicillin (Penbritin)
2nd most used penicillin
O
Amoxycillin (Amoxil)
Problem 3 - Range of Activity
Examples of Aminopenicillins Include:
Properties
• Active vs Gram +ve bacteria and Gram -ve bacteria which
do not produce b-lactamases
• Acid resistant and orally active
• Non toxic
• Sensitive to b-lactamases
• Increased polarity due to extra amino group
• Poor absorption through the gut wall
• Disruption of gut flora leading to diarrhoea
• Inactive vs. Pseudomonas aeruginosa
Problem 3 - Range of Activity
Prodrugs of Ampicillin (Leo Pharmaceuticals - 1969)
O
H
R=
NH2
C
CH2O
CMe3
PIVAMPICILLIN
C
C
H
N
O
H
H
S
O
Me
R=
TALAMPICILLIN
O
Me
N
O
O
CO2R
R=
CH
Me
O
C
O
CH2Me
BACAMPICILLIN
Properties
• 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
Problem 3 - Range of Activity
Mechanism
H
PEN
O
H
PEN
H
C
C O CH2 O
C O CH2
CMe3
ENZYME
C OH
O
O
O
O
•
•
•
PEN
Formaldehyde
Ester is less shielded by penicillin nucleus
Hydrolysed product is chemically unstable and degrades
Methyl ester of ampicillin is not hydrolysed in the
body - bulky penicillin nucleus acts as a steric shield
The aminopenicillins include Ampicillin (parenteral) as well as
Amoxicillin and Ampicillin (both oral)
Gram-positive bacteria
Streptococcus pyogenes,
Viridans streptococci,
Some Streptococcus
pneumoniae, Some
enterococci Listeria
monocytogenes
Gram-negative bacteria
Neisseria meningitidis,
Some Haemophilus
influenzae, Some
Enterobacteriaceae
Anaerobic bacteria
Clostridia spp. (except C.
difficile), Antinomyces
israelii
Spirochetes
Borrelia burgdorferi
b-Lactamase Inhibitors
Clavulanic acid (Beechams 1976)(from Streptomyces clavuligerus)
•
•
•
•
•
•
Weak, unimportant antibacterial activity
Powerful irreversible inhibitor of b-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
b-Lactamase Inhibitors
Clavulanic acid - mechanism of action
1
2
NH 2
NH 2
OH
3
4
5
b-Lactamase Inhibitors
Penicillanic acid sulfone derivatives
Sulbactam
•
•
•
•
•
Tazobactam
Suicide substrates for b-lactamase enzymes
Sulbactam has a broader spectrum of activity vs b-lactamases than
clavulanic acid, but is less potent
Unasyn = ampicillin + sulbactam
Tazobactam has a broader spectrum of activity vs b-lactamases than
clavulanic acid, and has similar potency
Tazocin or Zosyn = piperacillin + tazobactam
The aminopenicillins + b-lactamase inhibitor combinations include ampicillinsulbactam (parenteral) and amoxicillin-clavulanate (oral)
Gram-positive
bacteria
Some Staphylococcus aureus,
Streptococcus pyogenes,
Viridans streptococci, Some
Streptoocus pneumoniae, Some
enterococci Listeria
monocytogenes
Gram-negative
bacteria
Neisseria spp. Haemophilus
influenzae, Many
Enterobacteriaceae
Anaerobic
bacteria
Clostridia spp. (except C.
difficile), Actinomyces israellii,
Bacteroides spp.
Spirochetes
Borrelia burgdorferi
Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins
Class 2 - CO2H at the a-position (carboxypenicillins)
Examples
CO2R
CH
C
H
N
H
H
S
O
Me
R=H
R = Ph
CARBENICILLIN
CARFECILLIN
Me
N
O
CO2H
•
•
•
•
•
•
•
•
Carfecillin = prodrug for carbenicillin
Active over a wider range of Gram -ve bacteria than ampicillin
Active vs. Pseudomonas aeruginosa
Resistant to most b-lactamases
Less active vs Gram +ve bacteria (note the hydrophilic group)
Acid sensitive and must be injected
Stereochemistry at the a-position is important
CO2H at the a-position is ionised at blood pH
Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins
Class 2 - CO2H at a-position (carboxypenicillins)
Examples
CO2H
S
H H
N
O
H
N
O
S
Me
TICARCILLIN
Me
CO2H
•
•
•
•
•
•
Administered by injection
Identical antibacterial spectrum to carbenicillin
Smaller doses required compared to carbenicillin
More effective against P. aeruginosa
Fewer side effects
Can be administered with clavulanic acid
Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins
Class 3 - Urea group at the a-position (ureidopenicillins)
Examples
O
Azlocillin
Mezlocillin
HN
MeO2S
N
O
N
O
R2N
NH
N
H H
N
O
Piperacillin
•
•
•
•
•
•
Et N
N
O
O
H
N
O
S
Me
Me
CO2H
Administered by injection
Generally more active than carboxypenicillins vs. streptococci and
Haemophilus species
Generally have similar activity vs Gram -ve aerobic rods
Generally more active vs other Gram -ve bacteria
Azlocillin is effective vs P. aeruginosa
Piperacillin can be administered alongside tazobactam
The Extended Spectrum Penicillins include Piperacillin and Ticarcillin (parenteral)
as well as Carbenicillin (oral)
Gram-positive
bacteria
Streptococcus pyogenes, Viridans
streptococci, Some Streptococcus
pneumoniae, Some enterococci
Gram-negative
bacteria
Neisseria meningitidis, Some
Haemophilus influenzae, Some
Enterobacteriaceae,
Pseudomonas aeruginosa
Anaerobic
bacteria
Clostridia spp. (except C. difficile),
Some Bacteroides spp.
Extended-Spectrum Penicillin + b-Lactamase Inhibitor Combinations
include:Piperacillin-tazobactam as well as ticarcillin-clavulanate (both pairs are
parenteral)
Gram-positive
bacteria
Some Staphylococcus aureus,
Streptocosoccus pyogenes,
Viridans streptococci, Some
Streptococcus pneumoniae,
Some enterococci Listeria
monocytogenes
Gram-negative
bacteria
Neisseria spp. Haemophilus
influenzae, Most
Enterobacteriaceae,
Pseudomonas aeruginosa
Anaerobic
bacteria
Clostridia spp. (except C. difficile),
Bacteroides spp.
CEPHALOSPORINS
O
R
C
H
N
H
H
S
N
OAc
O
CO2H
1. Introduction
•
Antibacterial agents which inhibit bacterial cell wall synthesis
•
Discovered from a fungal colony in Sardinian sewer water
(1948)
•
Cephalosporin C identified in 1961
6. Mechanism of Action
H H
N
7
R
O
H
S
N
O
O
CO2H
•
C
O
Me
H
Enzyme
S
-CH3CO2O
N
O
O
Ser
OH
Ser
H H
N
R
CO2H
Enzyme
The acetoxy group acts as a good leaving group and aids the
mechanism
The Cephalosporins
Generation
Parenteral
Agents
Oral Agents
First-generation
Cefazolin
Cefadroxil, cephalexin
Second-generation
Cefotetan, cefoxitin,
cefuroxime
Cefaclor, cefprozil,
cefuroxime axetil,
loracarbef
Third-generation
Cefotaxime, ceftazidime,
ceftizoxime, ceftriaxone
Cefdinir, cefditoren,
cefpodoxime proxetil,
ceftibuten, cefixime
Fourth-generation
Cefepime
8. First Generation Cephalosporins
Cephalothin
H H
N
7
S
O
H
S
3
N
OAc
O
CO2H
•
•
•
•
•
•
•
•
•
First generation cephalosporin
More active than penicillin G vs. some Gram -ve bacteria
Less likely to cause allergic reactions
Useful vs. penicillinase producing strains of S. aureus
Not active vs. Pseudonomas aeruginosa
Poorly absorbed from GIT
Administered by injection
Metabolised to give a free 3-hydroxymethyl group
(deacetylation)
Metabolite is less active
8. First Generation Cephalosporins
Cephalothin - drug metabolism
H H
N
7
S
O
H
H H
N
S
3
N
O
CO2H
OAc
S
Metabolism
O
H
S
N
OH
O
CO2H
Less active
OH is a poorer leaving group
Strategy
• Replace the acetoxy group with a metabolically stable leaving
group
8. First Generation Cephalosporins
Cephaloridine
H H
N
7
S
O
H
S
3
N
N
O
CO2
•
The pyridine ring is stable to metabolism
•
The pyridine ring is a good leaving group (neutralisation of
charge)
•
Exists as a zwitterion and is soluble in water
•
Poorly absorbed through the gut wall
•
Administered by injection
8. First Generation Cephalosporins
Cefalexin
H2N
H
H H
N
7
O
H
S
3
N
Me
O
CO2H
•
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 a-carbon of the side chain
helps to compensate for the loss of activity due to the methyl
group
First Generation Cephalosporins
Cefazolin
Cefadroxil
Cefalexin
First Generation Cephalosporins include Cefazolin (parenteral) as well as
cefadroxil and cephalexin (oral).
Gram-positive
bacteria
Streptococcus pyogenes, Some
virdans streptococci, Some
Staphylococcus aureus, Some
Streptococcus pneumoniae
Gram-negative
bacteria
Some Eschericia coli, Some
Klebsiella pneumoniae, Some
Proteus mirabilis
9. Second Generation Cephalosporins
9.1 Cephamycins
H OMe H
N
HO2C
H2N
H
O
S
N
O
O
CO2H
C
NH2
Cephamycin C
O
•
Isolated from a culture of Streptomyces clavuligerus
•
First b-lactam to be isolated from a bacterial source
•
Modifications carried out on the 7-acylamino side chain
9. Second Generation Cephalosporins
9.1 Cephamycins
Cefoxitin
•
•
•
•
•
Broader spectrum of activity than most first generation
cephalosporins
Greater resistance to b-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.
9. Second Generation Cephalosporins
9.2 Oximinocephalosporins
Cefuroxime
•
•
•
•
•
•
Much greater stability against some b-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
• Second generation
• The second-generation cephalosporins have a
greater Gram-negative spectrum while retaining
some activity against Gram-positive cocci. They
are also more resistant to beta-lactamase.
•
•
•
•
Cefaclor (Ceclor, Distaclor, Keflor, Raniclor)
Cefonicid (Monocid)
Cefprozil (cefproxil; Cefzil)
Cefuroxime (Zinnat, Zinacef, Ceftin,
Biofuroksym)
• Cefuzonam
Forms of Cefuroxime
(2nd generation cephalosporin)
H OMe H
N
7
S
O
S
3
N
O
C
O
CO2H
Cefuroxime
(ZINACEF)
NH2
O
Cefuroxime axetil
(CEFTIN)
The Second-generation cephalosporins include Cefotetan, cefoxitin, and
cefuroxime (all parenteral) as well as Cefaclor, cefprozil, cefuroxime axetil, and
loracarbef (all oral).
Gram-positive
bacteria
True cephalosporins have activity
equivalent to first-generation
agents. Cefoxitin and cefotetan
have little activity
Gram-negative
bacteria
Escherichia coli, Klebsiella
pneumoniae, Proteus mirabilis,
Haemophilus influenzae,
Neisseria spp.
Anaerobic
bacteria
Cefoxitin and cefotetan have
moderate anaerobic activity.
10. Third Generation Cephalosporins
Oximinocephalosporins
R
Aminothiazole
ring
•
•
•
•
•
•
•
Aminothiazole ring enhances penetration of cephalosporins
across the outer membrane of Gram -ve bacteria
May also increase affinity for the transpeptidase enzyme
Good activity against Gram -ve bacteria
Variable activity against Gram +ve cocci
Variable activity vs. P. aeruginosa
Lack activity vs MRSA
Generally reserved for troublesome infections
10. Third Generation Cephalosporins
Oximinocephalosporins
Ceftazidime
•
•
•
•
Injectable cephalosporin
Excellent activity vs. P. aeruginosa and other Gram -ve
bacteria
Can cross the blood brain barrier
Used to treat meningitis
The Third-generation Cephalosporins include Cefotaxime, ceftazidime, ceftizoxime,
and ceftriaxone (all parenteral) as well as Cefdinir, cefditoren, cefpodoxime proxetil,
ceftibuten, and cefixime (all oral).
Gram-positive
bacteria
Streptococcus pyogenes, Viridans
streptococci, Many Streptococcus
pneumoniae, Modest activity against
Staphylococcus aureus
Gram-negative
bacteria
Escherichia coli, Klebsiella
pneumoniae, Proteus spp.
Haemophilus influenzae, Neisseria
spp. Some Enterobacteriaceae.
Anaerobic
bacteria
Atypical bacteria
Spirochetes
Borrelia burgorferi
11. Fourth Generation Cephalosporins
Oximinocephalosporins
R
•
•
•
•
•
•
Zwitterionic compounds
Enhanced ability to cross the outer membrane of Gram
negative bacteria
Good affinity for the transpeptidase enzyme
Low affinity for some b-lactamases
Active vs. Gram +ve cocci and a broad array of Gram -ve
bacteria
Active vs. P. aeruginosa
Fourth Generation Cephalosporins include cefepime (parenteral).
Gram-positive
bacteria
Streptococcus pyogenes, Viridans
streptococci, Many Streptocossus
pneumoniae. Modest activity against
Staphylococcus aureus
Gram-negative
bacteria
Escherichia coli, Klebsiella
pneumoniae, Proteus spp.
Haemophilus influenzae, Neisseria
spp. Many other Enterobacteriaceae,
Pseudomonas aeruginosa.
Anaerobic
bacteria
Atypical bacteria
Newer b-Lactam Antibiotics
Thienamycin (Merck 1976)(from Streptomyces cattleya)
•
•
•
•
•
Potent and wide range of activity vs Gram +ve and Gram -ve
bacteria
Active vs. Pseudomonas aeruginosa
Low toxicity
High resistance to b-lactamases
Poor stability in solution (ten times less stable than Pen G)
Newer b-Lactam Antibiotics
Thienamycin analogues used in the clinic
Imipenem
Meropenem
Ertapenem(2002)
The Carbapenems include Imipenem/cilstatin, Meropenem, and Ertapenem (all
parenteral)
Gram-positive
bacteria
Streptococcus pyogenes, Viridans
group streptococci, Streptococcus
pneumoniae, Modest activity
against Staphylococcus aureus,
Some enterococci, Listeria
monocytogenes
Gram-negative
bacteria
Haemophilus influenzae,
Neisseria spp.,
Enterobacteriaceae,
Pseudomonas aeruginosa
Anaerobic
bacteria
Bacteroides fragilis, Most other
anaerobes.
Newer b-Lactam Antibiotics
Clinically useful monobactam
Aztreonam
•
•
•
•
Administered by intravenous injection
Can be used for patients with allergies to penicillins
and cephalosporins
No activity vs. Gram +ve or anaerobic bacteria
Active vs. Gram -ve aerobic bacteria
The Monobactams include only Aztreonam, which is parenteral
Gram-positive
bacteria
Gram-negative
bacteria
Anaerobic
bacteria
Atypical bacteria
Haemophilus influenzae,
Neisseria spp. Most
Enterobacteriaceae, Many
Pseudomonas aeruginosa.
Vancomycin
Mechanism of Action of Vancomycin
Vancomycin binds to the D-alanyl-D-alanine dipeptide on the peptide side chain of
newly synthesized peptidoglycan subunits, preventing them from being
incorporated into the cell wall by penicillin-binding proteins (PBPs). In many
vancomycin-resistant strains of enterococci, the D-alanyl-D-alanine dipeptide is
replaced with D-alanyl-D-lactate, which is not recognized by vancomycin. Thus, the
peptidoglycan subunit is appropriately incorporated into the cell wall.
• http://student.ccbcmd.edu/courses/bio141/lecg
uide/unit2/control/vanres.html
Antimicrobial Activity of Vancomycin
Gram-positive
bacteria
Staphylococcus aureus,
Staphylococcus epidermidis,
Streptococcus pyogenes. Viridans
group streptococci, Streptococcus
pneumoniae, Some enterococci.
Gram-negative
bacteria
Anaerobic bacteria Clostridium spp. Other Grampositive anaerobes.
Atypical bacteria
Daptomycin
•
•
•
Daptomycin is a lipopeptide antibiotic
Approved for use in 2003
Lipid portion inserts into the bacterial cytoplasmic membrane where it forms
an ion-conducting channel.
Antimicrobial Activity of Daptomycin
Gram-positive
bacteria
Streptococcus pyogenes,
Viridans group streptococci,
Streptococcus pneumoniae,
Staphylococci, Enterococci.
Gram-negative
bacteria
Anaerobic
bacteria
Atypical
Some Clostridium spp.
Rifamycins
• Rifampin is the oldest and most widely used of the rifamycins
• Rifampin is also the most potent inducer of the cytochrome P450 system
• Therefore, Rifabutin is favored over rifampin in individual who are
simultaneously being treated for tuberculosis and HIV infection, since it will
not result in oxidation of the antiviral drugs the patient is taking
• Rifaximin is a poorly absorbed rifamycin that is used for treatment of
travelers’ diarrhea.
The Rifamycins include Rifampin, Rifabutin, Rifapentine, and Rifaximin, all of which
can be administered orally. Rifampin can also be administered parenterally.
Gram-positive
bacteria
Staphylococci
Gram-negative
bacteria
Haemophilus influenzae,
Neisseria meningitidis
Anaerobic
bacteria
Mycobacteria
Mycobacterium tuberculosis,
Mycobacterium avium complex,
Mycobacteriumleprae.
Aminoglycosides
The structure of the aminoglycoside amikacin. Features of
aminoglycosides include amino sugars bound by glycosidic linkages to a
relatively conserved six-membered ring that itself contains amino group
substituents.
Bacterial resistance to aminoglycosides occurs via one of three mechanisms
that prevent the normal binding of the antibiotic to its ribosomal target:
(1) Efflux pumps prevent accumulation of the aminoglycoside in the cytosol of
the bacterium.
(2) Modification of the aminoglycoside prevents binding to the ribosome.
(3) Mutations within the ribosome prevent aminoglycoside binding.
The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and
Amikacin (all parenteral), as well as Neomycin (oral).
Gram-positive
bacteria
Used synergistically against
some: Staphylococci,
Streptococci, Enterococci, and
Listeria monocytogenes
Gram-negative
bacteria
Haemophilus influenzae,
Enterobacteiaceae,
Pseudomonas aeruginosa
Anaerobic
bacteria
Atypical bacteria
Mycobacteria
Mycobacterium tuberculosis,
Mycobacterium avium complex.
Macrolides and Ketolides
The structures of erythromycin and
telithromycin Circled substituents
and distinguish telithromycin from
the macrolides. Substituent allows
telithromycin to bind to a second site
on the bacterial ribosome.
The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all
oral, with erythromycin and azithromycin also being available parenterally).
Gram-positive
bacteria
Some Streptococcus pyogenes. Some
viridans streptococci, Some
Streptococcus pneumoniae. Some
Staphylococcus aureus.
Gram-negative
bacteria
Neiseria spp. Some Haemophilus
influenzae. Bordetella pertussis
Anaerobic
bacteria
Atypical
bacteria
Chlamydia spp. Mycoplasma spp.
Legionella pneumophila, Some
Rickettsia spp.
Mycobacteria
Mycobacterium avium complex,
Mycobacterium leprae.
Spirochetes
Treponema pallidum, Borrelia
burgdorferi.
The related ketolide class consists of Telithromycin (oral).
Gram-positive
bacteria
Streptococcus pyogenes,
Streptococcus pneumoniae,
Some Staphylococcus aureus
Gram-negative
bacteria
Some Haemophilus influenzae,
Bordetella pertussis
Anaerobic
bacteria
Atypical bacteria
Chlamydia spp. Mycoplasma
spp. Legionella pneumophila
The Tetracycline Antibiotics
The structure of tetracycline
The Tetracycline Class of Antibiotics consists of Doxycycline and
Tigecycline (parenteral) as well as Tetracycline, Doxycycline and
Minocycline (oral)
Gram-positive
bacteria
Some Streptococcus pneumoniae
Gram-negative
bacteria
Haemophilus influenzae,
Neisseria meningitidis
Anaerobic
bacteria
Some Clostridia spp. Borrelia
burgdorferi, Treponema pallidum
Atypical bacteria
Rickettsia spp. Chlamydia spp.
Tigecycline
The antimicrobial activity of Tigecycline (parenteral)
Gram-positive
bacteria
Streptococcus pyogenes.
Viridans group streptococci,
Streptococcus pneumoniae,
Staphylococci, Enterococci,
Listeria monocytogenes
Gram-negative
bacteria
Haemophilus influenzae,
Neisseria spp.
Enterobacteriaceae
Anaerobic
bacteria
Bacteroides fragilis, Many other
anaerobes
Atypical bacteria
Mycoplasma spp.
Chloramphenicol
The Antimicrobial Activity of Chloramphenicol
Gram-positive
bacteria
Streptococcus pyogenes,
Viridans group streptococci.
Some Streptococcus pneumoniae
Gram-negative
bacteria
Haemophilus influenzae,
Neisseria spp. Salmonella spp.
Shigella spp.
Anaerobic
bacteria
Bacteroides fragilis. Some
Clostridia spp. Other anaerobic
Gram-positive and Gram negative
bacteria
Atypical bacteria
Rickettsia spp. Chlamydia
trachomatis, Mycoplasma spp.
Clindamycin
The Antimicrobial Activity of Clindamycin (both oral and
parenteral)
Gram-positive
bacteria
Some Streptococcus pyogenes,
Some viridans group streptococci.
Some Streptococcus
pneumoniae, Some
Staphylococcus aureus
Gram-negative
bacteria
Anaerobic
bacteria
Atypical bacteria
Some Bacteroides fragilis, Some
Clostridium spp. Most other
anaerobes.
Streptogramins
The Antimicrobial Activity of Quinupristin/Dalfopristin
(parenteral)
Gram-positive
bacteria
Gram-negative
bacteria
Anaerobic
bacteria
Atypical bacteria
Streptococcus pyogenes,
Viridans group streptococci,
Streptococcus pneumoniae,
Staphylococcus aureus, Some
enterococci.
The Oxazolidinones
The structure of Linezolide
The Antimicrobial Activity of Linezolid (both oral and
parenteral)
Gram-positive
bacteria
Gram-negative
bacteria
Anaerobic
bacteria
Atypical bacteria
Streptococcus pyogenes.
Viridans group streptococci,
Streptococcus pneumoniae,
Staphylococci, Enterococci.
The related ketolide class consists of Telithromycin (oral).
Gram-positive
bacteria
Gram-negative
bacteria
Anaerobic
bacteria
Atypical bacteria
The related ketolide class consists of Telithromycin (oral).
Gram-positive
bacteria
Gram-negative
bacteria
Anaerobic
bacteria
Atypical bacteria
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