Transcript b -Lactamase Inhibitors

b-Lactamase Inhibitors
Clavulanic acid (Beecham 1976)(from Streptomyces clavuligerus)
Sulphur replaced by O
No acylamino
side chain
H
9
O
5
6
7
N
1
OH
4
3
2
H
O
H
CO2H
b-Lactam
Oxazolidine ring
•
•
•
•
•
•
Weak, unimportant antibacterial activity
Powerful irreversible inhibitor of b-lactamases - suicide substrate
Used as a sentry drug for ampicillin
Augmentin = amoxicillin+ clavulanic acid
Allows less amoxicillin per dose and an increased activity spectrum
Timentin = ticarcillin + clavulanic acid
b-Lactamase Inhibitors
Augmentin = Amoxicillin + Clavulanic Acid
b-Lactamase Inhibitors
Penicillanic acid sulfone derivatives
O
S
O
6
5
7
N
•
•
•
S
Me
1
Me
3
CO2 Na
O
6
2
Sulbactam
•
•
O
O
N
Me
N
3
N
O
N
CO2
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 + 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 - aerobic rods
Generally more active vs other Gram - 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
Giussepe Brotzu noticed that the substance cultured from
the sewer water had activity against Salmonella typhi, the
active cause of typhoid fever
Typhoid fever is transmitted human to human by contact
with contaminated feces.
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 - 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 cefalexin (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
H OMe H
N
7
S
O
S
3
N
O
CO2H
•
•
•
•
•
O
C
NH2
Cefoxitin
O
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
Me
O
N
C
O
H H
N
O
H
N
O
O
CO2H
•
•
•
•
•
•
Cefuroxime
S
C
NH2
O
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)
Cefuroxime sodium
(ZINACEF)
Cefuroxime axetil
(CEFTIN)
More second generation cephalosporins:
Loracarbef (Lorabid)
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
Me
Aminothiazole
ring
O
N
H2N
S
N
C
H H
N
H
S
CH2S
N
N
O
Cefotaxime
Ceftizoxime
CH2OCOMe
H
Me
N
R
O
N
Ceftriaxone
OH
O
CO2H
•
•
•
•
•
•
•
Aminothiazole ring enhances penetration of cephalosporins across the outer
membrane of Gram - bacteria
May also increase affinity for the transpeptidase enzyme
Good activity against Gram - bacteria
Variable activity against Gram + cocci
Variable activity vs. P. aeruginosa
Lack activity vs MRSA
Generally reserved for troublesome infections
Ceftriazone (Rocephin) is a popular third
generation cephalosporin
It is the drug of choice for bacterial
meningitis
10. Third Generation Cephalosporins
Oximinocephalosporins
Me
Me
O
N
C
S
N
H 2N
CO2H
H H
N
O
H
S
N
N
O
CO2
Ceftazidime
•
•
•
•
Injectable cephalosporin
Excellent activity vs. P. aeruginosa and other Gram - 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
Me
O
N
H2N
S
R
N
C
H H
N
O
H
Me
S
N
N
R
O
CO2H
•
•
•
•
•
•
CH2
CH2 N
Cefipime
Cefpirome
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 + cocci and a broad array of Gram - 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)
Acylamino side
chain absent
OH
Plays a role
in ß-lactamase
resistance
Opposite
stereochemistry
to penicillins
Carbon
H
H
H3C
NH3
S
N
O
CO2
Double bond leading to
high ring strain and an increase
in b-lactam ring reactivity
Carbapenam nucleus
•
•
•
•
•
Potent and wide range of activity vs Gram + and Gram - 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
H OH
Me
O
H OH
Me
NH
HN
H
N
CO2
H
H
O
O
C
N
Me
Meropenem
S
N
Me
H
N
Me
O
H OH
Imipenem
S
CO2
H
H
N
Me
O
C
N
H
Ertapenem(2002)
S
N
CO2
CO2
Primaxin = Imipenem + Cilastatin
Cilastatin is an inhibitor of a
human enzyme, renal
dehydropeptidase, which
degrades carbapenems
Meropenem, Merrem,
AstraZeneca
Ertapenem, Invanz, Merck
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 + or anaerobic bacteria
Active vs. Gram - 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.