Download Some Streptococcus pneumoniae

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 DAla-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
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Step 1: Daptomycin binds to the cytoplasmic
membrane in a calcium-dependent manner
Step 2: Daptomycin oligomerizes, disrupting the
membrane
Step 3: The release of intracellular ions and rapid
death
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 (brand name Mycobutin) 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).
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
Doxycycline
Tigecycline
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 gastrointestinal
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
• Binds to the 50S subunit and prevents
association of this unit with the 30S
subunit.
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.
NH2
H2
C
OCH3
N
H2N
N
OCH3
OCH3
Sulfamethoxazole
Trimethoprim
•
This combination is known as co-trimoxazole, TMP-sulfa, or TMP-SMX
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)
Fluoroquinolones
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