Transcript Document 7226747

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
NH2
H
N
S
O
N
CH 3
O
CO2 Na
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
H OMe H
N
7
S
O
S
3
N
O
CO2H
•
•
•
•
•
Cefoxitin
O
C
NH2
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)
N
OCH 3
O
H
N
N
S
O
OCH 3
N
O
O
C
H2
O
H
N
S
O
O
O
N
O
O
CO2 Na
NH2
NH2
C
H2
H 3C
O
O
O
Cefuroxime
(ZINACEF)
O
CH 3
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
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 -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
Me
Me
O
N
C
S
N
H 2N
CO2H
H H
N
O
H
Ceftazidime
S
N
N
O
CO2
•
•
•
•
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
Me
O
N
H2N
S
R
N
C
H H
N
O
H
Me
S
N
CO2H
•
•
•
•
N
R
O
•
•
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 +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)
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 +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
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
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
Me
N
H2N
Me
O
H
N
N
S
CO2H
O
O
•
•
•
•
Me
Aztreonam
N
SO3-
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
Vancomycin is called a ‘glycopeptide’, meaning that it is a cyclic peptide, with
sugar residues attached to it.
Bacterial Cell Wall Synthesis (review)
•http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/ppgsynanim.html
Penicillin Mechanism of Action (review)
http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/penres.html
Vancomycin Mechanism of Action
• http://student.ccbcmd.edu/courses/bio141/
lecguide/unit2/control/vanres.html
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.
Vancomycin Uses
• Vancomycin is used to treat aerobic Gram +
bacteria, including MRSA and strains of
penicillin-resistant Streptococcus pneumoniae
• Vancomycin is administered intraveneously
• Vancomycin can also be used to treat anearobic
Gram + bacteria, including Clostridium difficile
(in the case of a GI infection, Vancomycin can
be administered orally).
• Vancomycin cannot be used to treat Gram –
bacteria, since the large size of the vancomycin
molecule prohibits its passing of the outer
membrane.
Vancomycin Resistance
• Some Enterococci have developed resistance to
vancomycin (Enterococcus faecium and Enterococcus
faecalis).
• These bacteria are called Vancomycin Resistant
Enterococci (VRE)
• The mechanism of resistance involves the
transformation of the D-Ala-D-Ala linkage in the peptide
side chain into D-Ala-D-Lac (i.e. replacement of the NH2
group by an OH group)
• This terminal linkage is still recognized by the essential
PBP’s (so the cell wall can still be constructed), but is not
recognized by vancomycin (thus resulting in resistance).
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 called a lipopeptide antibiotic
Approved for use in 2003
Lipid portion inserts into the bacterial cytoplasmic membrane where it forms
an ion-conducting channel.
Marketed under the trade name Cubicin
Uses of Daptomycin
• Daptomycin is active against many aerobic
Gram-positive bacteria
• Includes activity against MRSA, penicillinresistant Streptococcus pneumoniae, and some
vancomycin-resistant Enterococci (VRE)
• Daptomycin is not active against Gram negative
strains, since it cannot penetrate the outer
membrane.
• Primarily been used to treat skin and soft tissue
infections
• Poor activity in the lung.
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 individuals 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.
Mechanism of Action of Rifampin
• Rifampin inhibits transcription by inactivating bacterial
RNA polymerase
• Resistance develops relatively easily, and can result
from one of a number of single mutations in the
baqcterial gene that encodes RNA polymerase.
• Therefore, Rifampin is rarely used as monotherapy (i.e.
not used as a single agent) but usually combined with
other antibiotics
Uses of Rifampin
• Used, in combination with other drugs, to
treat Mycobacterium tuberculosis
• Used to treat some Staphylococcal
infections.
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.
Aminoglycoside Mechanism of
Action
• Aminoglycosides bind to the 30S subunit of the
bacterial ribosome, thereby inhibiting bacterial
protein synthesis (translation)
• http://www.microbelibrary.org/microbelibrary/files
/ccImages/Articleimages/kaiser/mechanisms/altri
bo_antibiot.html
• http://www.microbelibrary.org/microbelibrary/files
/ccImages/Articleimages/kaiser/mechanisms/altri
bo_antibiot.html
Uses of Aminoglycoside Antibiotics
• Unlike vancomycin, the aminoglycosides
have excellent activity against Gram –
aerobic bacteria
• Their extensive positive charge enables
them to bind to and penetrate the
negatively charged outer membrane and
get into the periplasm
• They are further transported into the
cytoplasm by a bacterial transport system.
Lipopolysaccharide is Part of the
Outer Membrane of Gram Negative
Bacteria
• Bacterial lipopolysaccharides are toxic to animals. When
injected in small amounts LPS or endotoxin activates
several host responses that lead to fever, inflammation and
shock. Endotoxins may play a role in infection by any Gramnegative bacterium. The toxic component of endotoxin (LPS)
is Lipid A. The O-specific polysaccharide may provide for
adherence or resistance to phagocytosis, in the same
manner as fimbriae and capsules. The O polysaccharide
(also referred to as the O antigen) also accounts for multiple
antigenic types (serotypes) among Gram-negative bacterial
pathogens. Thus, E. coli O157 (the Jack-in-the-Box and
Stock Pavillion E. coli) is #157 of the different antigenic types
of E. coli and may be identified on this basis.
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.
Mechanism of Action of Macrolide
Antibiotics
• Macrolides bind tightly to the 50S subunit of the
bacterial ribosome, thus blocking the exit of the
newly synthesized peptide
• Thus, they are interfering with bacterial
translation
• http://www.microbelibrary.org/microbelibrary/files
/ccImages/Articleimages/kaiser/mechanisms/altri
bo_antibiot.html
• http://www.microbelibrary.org/microbelibrary/files
/ccImages/Articleimages/kaiser/mechanisms/altri
bo_antibiot.html
Uses of Macrolide Antibiotics
• Active against a broad range of bacteria
• Effective against some stphylococci and
streptococci, but not usually used for
MRSA or penicillin-resistant streptococci
• Most aerobic Gram- bacteria are resistant
• Active against many atypical bacteria and
some mycobacteria and spirochetes
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.
Uses of Telithromycin (a ketolide)
• Telithromycin is approved for use against
bacterial respiratory infections
• Active against most strains of
Streptococcus pneumoniae, including
penicillin- and macrolide-resistant strains
• Also active against more strains of
Staphylococci
• Only available in oral formulation
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
Tetracycline Antibiotics
Tetracycline
Tigecycline
Doxycycline
Mechanism of Action of the
Tetracycline Antibiotics
• The tetracyclines bind to the 30S subunit
of the bacterial ribosome and prevent
binding by tRNA molecules loaded with
amino acids.
• http://student.ccbcmd.edu/courses/bio141/
lecguide/unit2/control/tetres.html
Uses of the Tetracycline Antibiotics
• Main use is against atypical bacteria,
including reckettsiae, chlamydiae, and
mycoplasmas
• Also active agains some aerobic Grampositive pathogens and some aerobic
Gram-negative bacteria
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
Mechanism of Action of
Chloroamphenicol
• Binds to the 50S subunit of the bacterial
ribosome, where it blocks binding of tRNA
Uses of Chloramphenicol
• Severe toxicity limits utility
• The most serious side effect of chloramphenicol
treatment is aplastic anaemia (a condition where
bone marrow does not produce sufficient new
cells to replenish blood cells)
• This effect is rare and is generally fatal: there is
no treatment and there is no way of predicting
who may or may not get this side effect.
• The effect usually occurs weeks or months after
chloramphenicol treatment has been stopped.
Uses of Chloramphenicol
• However, despite its toxicity,
chloramphenicol has a wide spectrum of
activity, that includes many aerobic Grampositive, Gram-negative, anaerobic, and
atypical bacteria
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
Mechanism of Action of
Clindamycin
• Clindamycin binds to the 50S subunit of
the ribosome to inhibit protein synthesis
Uses of Clindamycin
• Clindamycin is a member of the
lincosamide series of antibiotics
• Main utility is in treatment of Gram-positive
bacteria and anaerobic bacteria
• Active against staphylococcus, including
some strains of MRSA
• Not useful against Gram-negative bacteria
Toxicity of Clindamycin
• Clindamycin kills many components of the
gastrointestinalo flora, leaving only
Clostridium difficile
• This can result in overgrowth by C.
difficile, which is resistant
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
Mechanism of Action of
Streptogramins
• Dalfopristin inhibits the early phase of
protein synthesis in the bacterial ribosome
and quinupristin inhibits the late phase of
protein synthesis. The combination of the
two components acts synergistically and is
more effective in vitro than each
component alone.
Uses of the Streptogramins
• Have activity against Gram positive aerobic
bacteria
• Including MRSA, penicillin-resistant
Streptococcus pneumoniae and some VRE
(active against vancomycin resistant
Enterococcus faecelis, but not Enterococcus
faecium)
• The Quinupristin/Dalfopristin mixture is marketed
as Synercid
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
Mechanism of Action of the
Oxazolidinones
• Binds to the 50S subunit and prevents
association of this unit with the 30S
subunit.
• http://student.ccbcmd.edu/courses/bio141/
lecguide/unit6/genetics/protsyn/translation/
oxazolres_anim.html
Uses of the Oxazolidinones
• Has excellent activity against most aerobic
Gram-positive bacteria, including MRSA
and VRE.
• Only oxazolidonone on the market now is
Linezolid, which is both oral and
intravenous.
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 Sulfa Drugs
•Most commonly used sulfa drug is a mixture of the sulfa drug
Sulfamethoxazole and Trimethoprim
•These two drugs work in synergy, with the combination being superior to
either drug alone.
•This combination is known as co-trimoxazole, TMP-sulfa, or TMP-SMX
NH2
H2
C
OCH3
N
H2N
N
OCH3
OCH3
Sulfamethoxazole
Trimethoprim
Mechanism of Activity of Sulfa
Drugs
• Trimethoprim-sulfamethoxazole works by
preventing the synthesis of
tetrahydrofolate (THF), an essential
cofactor for the metabolic pathways that
generate deoxynucleotides, the building
blocks of DNA.
Tetrahydrofolic Acid Biosynthetic Pathway
• In the first step of the pathway, the sulfonamides are mistaken for the
natural substrate, p-aminobenzoic acid (PABA) and the drug acts as a
competitive inhibitor of this enzyme
• In a later step, the trimethoprim acts as a structural analog of dihydrofolate
and therefore inhibits dihydrofolate reductase
Structural Resemblance of Sulfamethoxazole and p-Aminobenzoic Acid
O
OH
H 2N
Sulfamethoxazole
p-Aminobenzoic Acid
Another sulfa drug is Dapsone, which is
used to treat Mycobacterium leprae
O
O
S
H2N
NH2
Dapsone
Structural Comparison of Two Sulfa
Drugs
The Antimicrobial Activity of the Sulfa Drugs
Gram-positive
bacteria
Some Sreptococcus pneumoniae,
Some Staphylococci, Listeria
monocytogenes
Gram-negative
bacteria
Some Haemophilus influenzae,
Some Enterobacteriaceae
Anaerobic
bacteria
Atypical bacteria
Mycobacteria
(Dapsone)
Mycobacterium leprae
The Fluoroquinolones
F
F
CO2H
N
Norf loxacin
(Noroxin)
N
Ciprof loxacin
(Cipro)
Ofloxacin
(Floxin)
O
O
F
NH
O
CH3
F
CO2H
N
N
Levof loxacin
(Maxaquin)
O
CH3
CO2H
N
N
N
O
F
CO2H
N
N
HN
Et
F
CO2H
N
N
HN
O
O
O
N
N
O
H 3C
Gatif loxacin
(Tequin)
CO2H
NH
N
O
H 3C
Moxif loxacin
(Avelox)
Mechanism of Action: Quinolones
• Quinolone antibiotics inhibit bacterial DNA
gyrase (Gram negative bacteria) or
Topoisomerase IV (Gram positive bacteria)
• http://canr.ca/images/Flash/fluoroquinolones.swf
Uses of the Quinolone Antibiotics
• Urinary Tract Infections: fluoroquinolones
are more effective than trimethoprimsulfamethoxazole
• Prostatitis
• Respiratory tract infections
• Gastrointestinal and Abdominal Infections
Antimicrobial Activity of the Quinolones (oral)
Gram-positive
bacteria
Some Staphylococcus aureus,
Streptococcus pyogenes, Virdans
group streptococci,
Streptococcus pneumoniae
Gram-negative
bacteria
Neisseria spp. Haemophilus
influenzae
Many Enterobacteriaceae, Some
Pseudomonas aeruginosa
Anaerobic
bacteria
Some clostridia spp, Some
Bacteroides spp.
Atypical bacteria
Chlamydia and Chlamydophilia,
Mycoplasma pneumoniae,
Legionella spp
Mycobacteria
Mycobacterium tuberculosis,
Mycobacterium avium complex,
Mycobacterium leprae
Metronidazole (Flagyl)
Metronidazole is used in the treatment of infections
caused by anaerobic bacteria
Metronidazole Mechanism of Action
Metronidazole is a prodrug. It is converted in anaerobic organisms by the redox
enzyme pyruvate-ferredoxin oxidoreductase. The nitro group of metronidazole is
chemically reduced by ferredoxin (or a ferredoxin-linked metabolic process) and
the products are responsible for disrupting the DNA helical structure, thus inhibiting
nucleic acid synthesis.
Mechanism of Action of
Metronidazole
• Metronidazole is selectively taken up by
anaerobic bacteria and sensitive protozoal
organisms because of the ability of these
organisms to reduce metronidazole to its
active form intracellularly.
Systemic metronidazole is indicated for the treatment of:
•
Vaginitis due to Trichomonas vaginalis (protozoal) infection in both symptomatic
patients as well as their asymptomatic sexual contacts;
•
Pelvic inflammatory disease in conjunction with other antibiotics such as
ofloxacin, levofloxacin, or ceftriaxone
•
Protozoal infections due to Entamoeba histolytica (Amoebic dysentery or
Hepatic abscesses), and Giardia lamblia (Giardiasis) should be treated alone or
in conjunction with iodoquinol or diloxanide furoate
•
Anaerobic bacterial infections such as Bacteroides fragilis, spp, Fusobacterium
spp, Clostridium spp, Peptostreptococcus spp, Prevotella spp, or any other
anaerobes in intraabdominal abscess, peritonitis, empyema, pneumonia,
aspiration pneumonia, lung abscess, diabetic foot ulcer, meningitis and brain
abscess, bone and joint infections, septicemia, endometritis, tubo-ovarian
abscess, or endocarditis
•
Pseudomembranous colitis due to Clostridium difficile
•
Helicobacter pylori eradication therapy, as part of a multi-drug regimen in peptic
ulcer disease
•
Prophylaxis for those undergoing potentially contaminated colorectal surgery
and may be combined with neomycin
Antimicrobial Activity of Metronidazole (both oral and
intravenous)
Gram-positive
bacteria
Gram-negative
bacteria
Anaerobic
bacteria
Atypical bacteria
Bacteroides fragilis, Clostridium
spp. Most other anaerobes
Antimicobacterial Agents
• Mycobacterial infections are very slow
progressing
• Many antibiotics have poor activity against
slow growing infections
• Mycobacteria must be treated for a long
time, and therefore, may readily develop
resistance to a single antibiotic
• Typically, several antibiotic agents are
used simultaneously
Antimycobacterial Agents
Pyrazinamide
Rifampin
CH2OH
H
N
N
H
CH2OH
Ethambutol
Mycobacterial Infections
http://www.nature.com/nrmicro/animation/imp_animation/index.html
http://web.uct.ac.za/depts/mmi/lsteyn/cellwall.html
Mycolic Acids provide protection
• Mycolic acids are long fatty acids found in the cell walls
of the mycolata taxon, a group of bacteria that includes
Mycobacterium tuberculosis, the causative agent of the
disease tuberculosis. They form the major component of
the cell wall of mycolata species.
• The presence of mycolic acids gives M. tuberculosis
many characteristics that defy medical treatment. They
lend the organism increased resistance to chemical
damage and dehydration, and prevent the effective
activity of hydrophobic antibiotics. In addition, the
mycolic acids allow the bacterium to grow readily inside
macrophages, effectively hiding it from the host's
immune system.
Mechanism of Action of AntiMycobacterial Antibiotics
• Rifampin is an inhibitor of RNA polymerase
• Isoniazide inhibits the synthesis of mycolic
acid
• Pyrazinoic acid inhibits the enzyme fatty acid
synthetase I, which is required by the
bacterium to synthesise fatty acids.
• Ethambutol disrupts the formation of the cell
wall