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/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 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 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 Staphylococcus aureus,

bacteria Staphylococcus epidermidis,
Streptococcus pyogenes. Viridans
group streptococci, Streptococcus
pneumoniae, Some enterococci.

Gram-negative
bacteria

Anaerobic bacteria Clostridium spp. Other Gram-

positive 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
Link
 Uses of Daptomycin
• Daptomycin is active against many aerobic
Gram-positive bacteria

• Includes activity against MRSA, penicillin-

resistant 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 Streptococcus pyogenes,

bacteria Viridans group streptococci,
Streptococcus pneumoniae,
Staphylococci, Enterococci.
Gram-negative
bacteria

Anaerobic Some Clostridium spp.

bacteria

Atypical
 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 Staphylococci
bacteria

Gram-negative Haemophilus influenzae,

bacteria 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
• Link
• Link
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 Gram-
negative 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 Used synergistically against

bacteria some: Staphylococci,
Streptococci, Enterococci, and
Listeria monocytogenes
Gram-negative Haemophilus influenzae,
bacteria 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/ccImag
es/Articleimages/kaiser/mechanisms/altribo_antibiot.html
• http://www.microbelibrary.org/microbelibrary/files/ccImag
es/Articleimages/kaiser/mechanisms/altribo_antibiot.html
• 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).

Clariithromycin
Erythromycin
 Azithromycin

Link
The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all
oral, with erythromycin and azithromycin also being available parenterally).

Gram-positive Some Streptococcus pyogenes. Some

bacteria viridans streptococci, Some
Streptococcus pneumoniae. Some
Staphylococcus aureus.
Gram-negative Neiseria spp. Some Haemophilus
bacteria influenzae. Bordetella pertussis

Anaerobic
bacteria
Atypical Chlamydia spp. Mycoplasma spp.
bacteria 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
Telithromycin
The related ketolide class consists of Telithromycin (oral).

Gram-positive Streptococcus pyogenes,

bacteria Streptococcus pneumoniae,
Some Staphylococcus aureus

Gram-negative Some Haemophilus influenzae,

bacteria 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 Gram-
positive 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 Some Streptococcus pneumoniae

bacteria

Gram-negative Haemophilus influenzae,

bacteria Neisseria meningitidis

Anaerobic Some Clostridia spp. Borrelia

bacteria burgdorferi, Treponema pallidum

Atypical bacteria Rickettsia spp. Chlamydia spp.

Tigecycline
The antimicrobial activity of Tigecycline (parenteral)

Gram-positive Streptococcus pyogenes.

bacteria Viridans group streptococci,
Streptococcus pneumoniae,
Staphylococci, Enterococci,
Listeria monocytogenes
Gram-negative Haemophilus influenzae,
bacteria Neisseria spp.
Enterobacteriaceae

Anaerobic Bacteroides fragilis, Many other

bacteria 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 Gram-
positive, Gram-negative, anaerobic, and
atypical bacteria
The Antimicrobial Activity of Chloramphenicol

Gram-positive Streptococcus pyogenes,

bacteria Viridans group streptococci.
Some Streptococcus pneumoniae

Gram-negative Haemophilus influenzae,

bacteria Neisseria spp. Salmonella spp.
Shigella spp.

Anaerobic Bacteroides fragilis. Some

bacteria 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 Some Streptococcus pyogenes,

bacteria Some viridans group streptococci.
Some Streptococcus
pneumoniae, Some
Staphylococcus aureus
Gram-negative
bacteria

Anaerobic Some Bacteroides fragilis, Some

bacteria Clostridium spp. Most other
anaerobes.

Atypical bacteria
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 Streptococcus pyogenes,

bacteria Viridans group streptococci,
Streptococcus pneumoniae,
Staphylococcus aureus, Some
enterococci.
Gram-negative
bacteria

Anaerobic
bacteria

Atypical bacteria
 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 Streptococcus pyogenes.

bacteria Viridans group streptococci,
Streptococcus pneumoniae,
Staphylococci, Enterococci.
Gram-negative
bacteria

Anaerobic
bacteria

Atypical bacteria
 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

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 Some Sreptococcus pneumoniae,

bacteria Some Staphylococci, Listeria
monocytogenes

Gram-negative Some Haemophilus influenzae,

bacteria Some Enterobacteriaceae

Anaerobic
bacteria

Atypical bacteria

Mycobacteria Mycobacterium leprae

(Dapsone)
 The Fluoroquinolones
O O
O
F CO2H F CO2H
F CO2H

N N N N
N N
HN N O
HN Et CH3

Norf loxacin Ciprof loxacin Ofloxacin

(Noroxin) (Cipro) (Floxin)

O O
O
F CO2H F CO2H
F CO2H

N N N N
N N
NH O NH O
N O H 3C
H 3C
CH3

Levof loxacin Gatif loxacin Moxif loxacin

(Maxaquin) (Tequin) (Avelox)
Fluoroquinolones
 Mechanism of Action: Quinolones
• Quinolone antibiotics inhibit bacterial DNA
gyrase (Gram negative bacteria) or
Topoisomerase IV (Gram positive
bacteria)
• http://can-
r.ca/images/Flash/fluoroquinolones.swf
 Uses of the Quinolone Antibiotics
• Urinary Tract Infections: fluoroquinolones
are more effective than trimethoprim-
sulfamethoxazole
• Prostatitis
• Respiratory tract infections
• Gastrointestinal and Abdominal Infections
Antimicrobial Activity of the Quinolones (oral)

Gram-positive Some Staphylococcus aureus,

bacteria Streptococcus pyogenes, Virdans
group streptococci,
Streptococcus pneumoniae
Gram-negative Neisseria spp. Haemophilus
bacteria influenzae
Many Enterobacteriaceae, Some
Pseudomonas aeruginosa
Anaerobic Some clostridia spp, Some
bacteria 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 Bacteroides fragilis, Clostridium

bacteria spp. Most other anaerobes

Atypical bacteria
 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 Anti-
Mycobacterial 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