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Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 19
ANTIBACTERIAL AGENTS
Part 3: Other lactams
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Carbapenems
• Thienamycin
• Imipenem
• Meropenem
• Ertapenem Core structure of the carbapenem molecules
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Oppositestereochemistry to penicillins
Newer β-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 β-lactamases
• Poor stability in solution (ten times less stable than Pen G)
CarbonPlays a rolein ß-lactamaseresistance
O
N
S
OH
H3C
CO2
H
NH3
H
Double bond leading to high ring strain and an increasein -lactam ring reactivity
Acylamino sidechain absent
Carbapenam nucleus
S
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Newer β-Lactam Antibiotics
Thienamycin analogues used in the clinic
NO
H
S
HN
CO2
OH
Me
HNH
Imipenem
aminomethylideneamino
1. Produced by the bacteria Streptomyces
cattleya .
2. Broad spectrum of activity aerobic and
anaerobic Gram positive as well as Gram
negative bacteria.
3. It is particularly important for its activity
against Pseudomonas aeruginosa and the
Enterococcus species.
4. It is not active against methicillin-resistant
Staphylococcus aureus.
N-Formimidoyl derivative of
thienamycin
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Imipenem
dehydropeptidase
metabolites
DHP= dehydropeptidases
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Meropenem (Merrem) MEROTROL
NO
H
S
CO2
OH
Me
H
HN C
N
O
Me
Me
H
1. Ultra-broad spectrum injectable antibiotic used to treat a wide
variety of infections, including meningitis and pneumonia.
2. Penetrates well into many tissues and body fluids including the
cerebrospinal fluid, bile, heart valves, lung, and peritoneal fluid
pyrrolidin-2-yl-sulfanyl
Carbapenam nucleus
CH3
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Meropenem MEROTROL
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Ertapenem • IV
• First-line treatment for community-acquired infections
• Effective against Gram negative bacteria. It is not active against MRSA, ampicillin-resistant enterococci, Pseudomonas aeruginosa or Acinetobacter species.
• Clinically useful activity against anaerobic bacteria.
pyrrolidin-2-yl-sulfanyl
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Doribax (Doripenem)
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Doripenem and Ertapenem
(A) The structures of Doripenem and Ertapenem. (B) The chemical mechanism
of hydrolysis of Ertapenem by the Mycobacterium tuberculosis BlaC.
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Stability toward
dehydropeptidase
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Carbapenems
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Newer β-Lactam Antibiotics
Monobactams
• Monocyclic β-Lactams:
–Nocaridicin
–Aztreonam
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Newer β-Lactam Antibiotics
Nocardicins (Fujisawa 1975)
• Monocyclic -lactam ring - monobactams
• Moderately active in vitro vs narrow group of Gram -ve bacteria
• Active vs. Pseusomonas aeruginosa
• Inactive vs. Gram +ve bacteria
• Different spectrum of activity from penicillins
• Thought to operate by a different mechanism from penicillins
• Low toxicity
Nocardicin A
DCO
N
CHN
H
N
C
CO2H
O
OH
CH2CH2 OHHC
HO2C
H2N
H
O
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Newer β-Lactam Antibiotics
Clinically useful monobactam
• 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
Aztreonam N
O
HN
O
SO3-
Me
NO
CO2HMeMe
N
S
H2N
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β-Lactamase Inhibitors
Clavulanic acid (Beechams 1976) (from Streptomyces clavuligerus)
• Weak, unimportant antibacterial activity
• Powerful irreversible inhibitor of β-lactamases - suicide
substrate
• Used as a sentry drug for Amoxicillin
• Augmentin = Amoxicillin + clavulanic acid
• Allows less Amoxicillin per dose and an increased activity
spectrum
• Timentin = Ticarcillin + Clavulanic acid
No acylaminoside chain
Sulphur replaced by O
-Lactam
9
2
53
4
17
6
H
CO2H
O
N
OH
OH
H
Acyl side
chain
-Lactam
ring
Thiazolidine
ring
N
S Me
Me
HN
H H
CO2HO
C
O
R
Oxazolidine ring
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2
N H 2
CH2OHO
HN
O
O
CO2H
BaseH
Clavulanic acid - mechanism of action
O H
N H 2
1
H
5
NH
CH
O
HC
O
Irreversibly blocked
4
H
CH2OH
CO2H
O
O
H2N
O
NH
3
CH2OH
CO2H
O
O
HN
O
NH
H
β-Lactamase Inhibitors
C H 2 O H
C O 2 H
O
N
O
OH
O
NH2
HO
O
2-Amino-5-hydroxy-3-oxopentanoic acid
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Clavulanic acid NXL104
Avibactam (NXL104)
NXL104
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Penicillanic acid sulfone derivatives
• Suicide substrates for -lactamase enzymes
• Sulbactam has a broader spectrum of activity vs -lactamases
than clavulanic acid, but is less potent
• Unasyn = ampicillin + sulbactam
• Tazobactam has a broader spectrum of activity vs -lactamases
than Clavulanic acid, and has similar potency
• Tazocin or Zosyn = piperacillin + tazobactam
β-Lactamase Inhibitors
N
O
S
CO2
OO
Me
Me
Na
N
O
S
CO2
OO
Me
N
NN
1
2
3
56
7
6
3
Sulbactam Tazobactam
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Olivanic Acids
MM 13902
Naturally occurring carbapenem -lactamase inhibitors with
antibacterial activity, produced by Streptomyces olivaceus
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NH2H3C
OOH
L-Alanine
NH2H3C
OOH
D-Alanine
RacemaseHN O
HO
NH2
O
D-Alanine-D-Alanine
D-Ala-D-Ala
Ligase
X
• Separated from Streptomyces garyphalu
• Acts at the cytoplasm
• It mimics the structure of D-Ala Prevent formation of D-Ala-D-Ala
• Inhibits the enzyme L-Alanine Racemase and the D-Ala-D-Ala
Ligase. (enzymes important in the cytosolic stages of
peptidoglycan synthesis) responsible for linking the two d-alanine
units together)
X
Used in the treatment of tuberculosis
D-4-amino-3-isoxazolidone
D-Cycloserine
Other drugs which act on bacterial cell wall biosynthesis
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D-AlanineTRANSPEPTIDASE
PENICILLIN
SUGARBACKBONE
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
SUGARBACKBONE
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 linking
Mechanism of action - bacterial cell wall synthesis
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Glycopeptides: VANCOMYCIN FAMILY
Isolated
Streptomyces orientalis
Used in the prophylaxis and treatment of infections caused by Gram-
positive bacteria (narrow-spectrum bactericidal glycopeptide)
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Crystal structure
• The short peptide (L-Lysyl-D-Alanyl-D-Alanine), which is a
bacterial cell wall precursor, bound to Vancomycin through five
hydrogen bonds indicated by the dotted lines.
James R. Knox and R. F. Pratt in Antimicrobial Agents and Chemotherapy, Year 1990, Volume
34, Issue 7, Pages 1342-1347.
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VANCOMYCIN: Structure and Mechanism of Action
Because vancomycin is a large molecule, it caps
the tails and acts as a steric shield, blocking
access to the transglycosidase and
transpeptidase enzymes.
Because vancomycin is such a large molecule, it
is unable to cross the outer cell membrane of
Gram -ve bacteria, lacks activity against those
organisms. It is also unable to cross the inner
cell membrane of Gram +ve bacteria, but this is
not required as the construction of the cell wall
takes place outside the cell membrane
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Capping Mechanism
Transglycosylation
The transfer of a sugar residue from
one glycoside to another (bond
formation, particularly during
polysaccharide synthesis)
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Dimerization of VANCOMYCIN
4 H-Bonds
5 H-Bonds
5 H-Bonds
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VANOMYCIN: Biosynthesis
Reactions involved in the biosynthesis of vancomycin.
Vancomycin is derived biosynthetically from a linear heptapeptide containing five
aromatic residues.
These undergo oxidative coupling with each other to produce three cyclic moieties
within the structure.
Chlorination, hydroxylation, and the final addition of two sugar units then
complete the structure
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Resistance to VANCOMYCIN
Vancomycin does not bind to D-Ala-D-Lac, which
leads to vancomycin resistance
Modification of the pentapeptide chain leading to resistance
Resistance has arisen from a modification of the cell wall
precursors where the terminal d-alanine group in the
pentapeptide chain has been replaced by d-lactic acid, resulting in
a terminal ester link rather than an amide link. This removes one
of the NH groups involved in the hydrogen bonding interaction
with vancomycin.
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β-D-glucosamine
Teicoplanins: Mixture of 5 major
constituents and four minor (named
Teicoplanin RS-1 through RS-5)
Th e teicoplanins belong to the vancomycin
family but do not dimarize
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Teicoplanin-A2-5
• Teicoplanin A2-5 is used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis.
Its mechanism of action
is to inhibit bacterial
cell wall synthesis.
Teicoplanin is marketed
by Aventis under the
trade name Targocid®.
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Binding Mode of Teicoplanin
Teicoplanins belong to the vancomycin family but do not dimarize.
The long alkyl chain plays an importart role is anchoring the
antibiotic to the outer surface of the cell membrane where it is
perfectly placed to interact with the building blocks for cell wall
synthesis.
Teicoplanin is used clinically for the treatment of Gram-positive
infections and is less toxic than vancomycin.
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Eremomycin and Y33328
LY33328 is 1000 times > active than vancomycin
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Removal of a tetrahydropyran ring to leave an alcohol group (R 4 ),
modification of the hydrophobic tail (R 2 ) and addition of a side
chain with a phosphate group (R 3 ), to give telavancin , which was
approved in 2009.
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Simplification of Natural Products
This lead compound: Capable of binding to D-Ala-D-Ala and D-Ala-D-Lac
• The complexity of the glycopeptides is an advantage in their targeting and
selectivity, it is a problem when it comes to synthesizing analogues.
• Therefore, work has been carried out to try and prepare simplified
• analogues of vancomycin which are easier to synthesize, yet retain the desired
selectivity.
• Structures such as those have been prepared which are capable of binding to
d-Ala -d-Ala and d-Ala-d-Lac
• These now represent lead compounds for the development of future
antibacterial agents
Simplified
analogues of
the
glycopeptides
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There are another two mechanisms by which glycopeptides
may have an antibacterial activity
Firstly, it is possible that glycopeptide dimers disrupt the cell
membrane structure. This is supported by the fact that
glycopeptide antibacterial agents enhance the activity of
aminoglycosides by increasing their absorption through the
cell membrane.
Secondly, RNA synthesis is known to be disrupted in the
presence of glycopeptides. The possibility of three different
mechanisms of action explains why bacteria are slow to
acquire resistance to the glycopeptides.
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Bacitracin
• Bacitracin interferes with the dephosphorylation of the C55-isoprenyl pyrophosphate, a molecule which carries the building blocks of the peptidoglycan bacterial cell wall outside of the inner membrane
• Bacitracin is Cyclic polypeptide complex produced Bacillus subtilis.
• Isolated in 1943 from a knee scrape from a girl named Margaret Tracy
• Binds to the lipid carrier responsible for transporting the
NAM/pentapeptide unit across the cell membrane, thus preventing it
from carrying out that role.
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Summary
β-Lactamase inhibitors are β-lactam structures that have negligible
antibacterial activity but inhibit β-lactamases. They can be
administered alongside penicillins to protect them from β-lactamases
and to broaden their spectrum of activity.
Carbapenems and monobactams are examples of other β-lactam
structures with clinically useful antibacterial activity.
Glycopeptides, such as vancomycin, bind to the building blocks for
cell wall synthesis, preventing their incorporation into the cell wall.
They also block the cross-linking reaction for those units already
incorporated in the wall. The glycopeptides are the drugs of last
resort against drug-resistant strains of bacteria.
Bacitracin binds to and inhibits the carrier lipid responsible for
carrying the cell wall components across the cell membrane.
Cycloserine inhibits the synthesis of D-Ala-D-Ala.