Definitions
• Bacteremia: Presence of bacteria in the
blood
• Under normal circumstances, the blood is
a sterile environment
Systemic Inflammatory Response
Syndrome (SIRS)
• An inflammatory response, to a wide variety
of clinical insults, characterized by two or
more of the following:
–
–
–
–
Temperature greater than 38 oC (100.4 oF)
Heart rate greater than 90 beats per min
Respiratory rate greater than 20 breaths per min
White blood cell count greater than 12,000/mL
Sepsis
Sepsis is a systemic inflammatory
response to a documented infection
In addition to preceding criteria, at least one of
the following must be present:
Alteration in mental state
Hypoxemia (lower pressure of oxygen in blood)
Elevated plasma lactate
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.
Allergic Responses to
Antibiotics
• Uticaria: A skin rash involving dark red
itchy bumps.
Allergic Responses
• Anaphylaxis: A severe, life-threatening allergic response,
having many potential manifestations, including loss of
consciousness, labored breathing, swelling of the
tongue, low blood pressure, etc.
Shock
• Shock is characterized by low blood pressure
(hypotension) and tachycardia
• Septic shock is a result of the infection itself (bacteremia,
sepsis).
• Anaphylactic shock is an allergic response to a foreign
agent (antibiotic, bee sting, etc.)
Vancomycin
Carbohydrate
Peptide Linkages
Vancomycin is called a ‘glycopeptide’, meaning that it is a
cyclic peptide, with sugar residues attached to it.
Discovery
Vancomycin was discovered in a soil
sample sent to the pharmaceutical company
Eli Lilly by a missionary in Borneo in the
1950’s.
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/lecgui
de/unit2/control/vanres.html
• Link
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 most often administered intravenously
• 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
amide NH by an O)
• 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
Lipophilic Tail
• 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
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
Link
Uses of Daptomycin (Cubicin)
• 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 (complicated skin and skin structure
infections, including MRSA).
• Also approved for S. aureus bloodstream
infections (bacteremia), including those with
right-sided infective endocarditis
• Poor activity in the lung, thus not used for
pneumonia
• Cubicin (Daptomycin) is administered
intravenously.
• It is not orally bioavailable.
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
•
The Rifamycins
Rifampicin
(Rifampin)
Rifapentine
(Priftin)
Rifabutin
(Mycobutin)
Rifaximin
(Xifaxan (US), Spiraxin (EU))
• 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.
• Rifampin and the
other rifamycins are
orally bioavailable.
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)
• Link
• LINK
• Link
The ribosome target of aminoglycosides is a
combination of RNA (below) and proteins
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.
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 (topical, oral).
Aminoglycosides
Streptomycin
Streptomycin was the first aminoglycoside to be discovered
(1944) and it still valuable (in combination with other
antibacterial agents) in the treatment of multidrug resistant
tuberculosis (although not a first line drug for tuberculosis)
Aminoglycosides
Gentamicin
•Gentamicin is most commonly used of the aminoglycosides
•Active against aerobic Gram-negative infections (and
sometimes Gram positive)
•Can be used synergistically, together with a cell wall targeting
agent (e.g. a penicillin)
•Available in parenteral, opthalmic, and topical formulations
Aminoglycosides
Tobramycin
•Tobramycin has better activity against Pseudomonas
aeruginosa than does gentamicin
•Tobramycin may be given either intramuscularly or
intravenously
•It is also administered by inhaler, particularly useful for
individuals with cystic fibrosis (frequently contract P.
aeruginosa infections)
Amikacin
• Amikacin has the broadest antimicrobial spectrum of the
aminoglycosides
• It is more resistant to aminoglycoside-inactivating enzymes
than the other aminoglycosides
• It is often used in hospitals where gentamicin- and
tobramycin-resistant microorganisms are prevalent
Neomycin
• Neomycin is widely used for topical administration
• Like other aminoglycosides, it is not absorbed well
orally, and is used to prepare the bowel for surgery.
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.
Chemical Definitions
Ester Linkage
Cladinose Sugar
• Macrolide = macrocyclic lactone (cyclic
ester)
• Macrolide antibiotics usually have ring
sizes of 14, 15, or 16 atoms
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
• Link
• Link
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).
Erythromycin
Clariithromycin
Erythromycin reactions under
acidic conditions
Clarithromycin substitutes a methoxy
group for the hydroxy and improves
acid stability
Methoxy group
Hydroxy group
Erythromycin
(14 membered ring)
Clariithromycin
(14 membered ring)
Insertion of ‘N’ into the ring
Azithromycin
(15 membered ring)
Link
LInk
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
Cladinose sugar replaced by ketone
Telithromycin: A ketolide
(14 membered ring)
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.
• LINK
Uses of the Tetracycline Antibiotics
• Main use is against atypical bacteria,
including rickettsia, chlamydia, and
mycoplasmas
• Also active against 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.
• Link
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.
• LINK
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
•LINK
•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
The Target of Trimethoprim is
Dihydrofolate Reductase (DHFR)
Inhibitors of Dihydrofolate
Reductase (DHFR)
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)
• Link
• LINK
• LINK
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
envelope 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.
Mycobacterium Cell Wall
Mechanism of Action of AntiMycobacterial Antibiotics
• Rifampin is an inhibitor of RNA polymerase
• Isoniazide inhibits the synthesis of mycolic acid
Mechanism of Action of Isoniazid
isoniazid
NADH
Isoniazid is a produg, that is activated by a mycobacterial
peroxidase, called KatG to form a reactive free radical, which, in
turn, reacts with NADH to form a covalent adduct. The reactive
(isoniazid-derived) species is probably an acyl radical (shown)
Mechanism of Action of Isoniazid
This isoniazid-NADP adduct then forms a complex with bacterial
enoyl reductase (InhA),an enzyme responsible for reducing
double bonds during fatty acid synthesis
• Pyrazinoic acid inhibits the enzyme fatty
acid synthetase I (FAS I), which is
required by the bacterium to synthesise
fatty acids.
• Ethambutol disrupts the formation of the cell
envelope by interfering with the enzyme that forms
the arabinogalactan polysaccharide (called
arabinogalactan transferase)
Arabinogalactan
D-Galactose
• Arabinogalactan is a biopolymer consisting of
arabinose and galactose monosaccharides
Arabinogalactan-mycolic acid adduct
Targets of First Line anti-TB Drugs
Overview of anti-mycobacterial drugs
Antimicrobial Resistance
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Assigned Reading:
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Antibiotic Basics for Clinicians, by Alan R. Hauser, pp. 33—99
Kirkpatrick Peter; Raja Aarti; LaBonte Jason; Lebbos John Daptomycin. Nature reviews. Drug
discovery (2003), 2(12), 943-4.
Ammerlaan, H. S. M.; Bonten, M. J. M. Daptomycin: graduation day. Clinical Microbiology and
Infection (2006), 12(Suppl. 8), 22-28.
Baltz, Richard H.; Miao, Vivian; Wrigley, Stephen K. Natural products to drugs: Daptomycin and
related lipopeptide antibiotics. Natural Product Reports (2005), 22(6), 717-741. pp. 717-722, 725726.
Baltz Richard H Daptomycin: mechanisms of action and resistance, and biosynthetic engineering.
Current opinion in chemical biology (2009), 13(2), 144-51. Journal code: 9811312.
Clay Kimberly D; Hanson John S; Pope Scott D; Rissmiller Richard W; Purdum Preston P 3rd; Banks
Peter M Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature
review. Annals of internal medicine (2006), 144(6), 415-20.
Zeitlinger, Markus; Wagner, Claudia Christina; Heinisch, Birgit. Ketolides - the modern relatives of
macrolides : the pharmacokinetic perspective. Clinical Pharmacokinetics (2009), 48(1), 23-38.
Vicens, Quentin; Westhof, Eric. RNA as a drug target: The case of aminoglycosides.
ChemBioChem (2003), 4(10), 1018-1023.
Wilson, Daniel N.; Nierhaus, Knud H. The oxazolidinone class of drugs find their orientation on the
ribosome. Molecular Cell (2007), 26(4), 460-462.
Marchese, A.; Schito, G. C. The oxazolidinones as a new family of antimicrobial agent. Clinical
Microbiology and Infection (2001), 7(Suppl. 4), 66-74.
Asaka, Toshifumi; Manaka, Akira; Sugiyama, Hiroyuki. Recent developments in macrolide
antimicrobial research. Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates)
(2003), 3(9), 961-989. [READ ONLY PP. 961-966 AND 981-983]
Zhanel, George G.; Homenuik, Kristen; Nichol, Kim; Noreddin, Ayman; Vercaigne, Lavern; Embil,
John; Gin, Alfred; Karlowsky, James A.; Hoban, Daryl J. The glycylcyclines: a comparative review
with the tetracyclines. Drugs (2004), 64(1), 63-88. [Read pp. 64-72]
Homework Questions:
1. To which site on the ribosome do the aminoglycoside antibiotics bind?
2. A high level of aminoglycoside resistance is known to result from the A1408G
mutation in bacterial ribosomes. A potential solution would be to design
aminoglycosides that can bind more tightly to this mutation. Why can’t this be
achieved?
3. Discuss the advantages and the disadvantages of using RNA as a drug target.
4. The activity o f daptomycin is highly dependent on which alkaline earth metal?
What is the function of this metal in the mechanism of action (MOA) of
daptomycin?
5. At which ribosomal site do the oxazolidinones bind? What accounts for their
side effects in patients undertaking prolonged treatment with these drugs?
6. Why is azithromycin currently considered one of the best of the macrolides?
7. Explain how tetracyclines gain access to the cytoplasm of Gram-negative
bacteria.