Diana
Marra
Oram, PhD
Office 9211
doram@umaryland.edu
Please read chapter 20 in your textbook Medical Microbiology
Use of antimicrobials by primitive peoples
There is evidence of successful chemotherapy in
ancient Peru
-
Use of bark from the cinchona tree to
treat malaria.
Many of the salves used by primitive peoples contained
antibacterial and antifungal substances.
1935 Use of protosil
(cleaved in the body to produce sulfanilamide
–
the first
sulfa drug)
to protect mice from streptococcal infection
Fleming isolated penicillin in 1929 but did not initially appreciate the
magnitude of the discovery
In 1939 Florey and colleagues at Oxford University again isolated penicillin
1944 Waksman isolates streptomycin and subsequently finds agents such
as chloramphenicol, tetracyclines, and erythromycin in soil samples.
1960s Advances in medicinal chemistry permit the synthesis of many new
chemotherapeutic agents by molecular modification of existing
compounds.
Development of new antibacterial agents has moved quickly, but
development of antifungal and antiviral agents has been slow.
Amphotericin B, isolated in the 1950s, remains an effective antifungal agent,
although newer agents such as fluconazole are now widely used.
Nucleoside analogs such as acyclovir have proved effective in the
chemotherapy of selected viral infections.
Antimicrobial Chemotherapy Harold C. Neu
and Thomas D. Gootz
Antibacterial Spectrum (2 types)
Broad
Can inhibit the growth of a wide variety of Gram +
and Gram
–
bacterial species
Narrow
Is only active against a limited variety of bacteria
Broad spectrum
Tetracycline and carbapenems active against many
Gram
-
positive and Gram negative bacteria
Often used for empirical or “blind” treatment of
infections when the causative agents are unknown (but
likely to be bacterial).
Blind treatments aren’t usually done anymore unless you’re on ur deathbed bc you
can induce resistance. Not saying that this treatment is bad, but these days we want
to understand what’s causing the disease/infection and know that the antibiotic
we’re prescribing will actually treat it.
Narrow spectrum
–
specific target
Penicillin effective only against Gram
-
positive bacteria
Metronidazole effective against strict anaerobes and
some protozoa.
Bacteriostatic
Inhibits the growth of an organism
Bactericidal
Kills an organism
Antibiotic Combinations
Synergism
Combination of antibiotics that has enhanced antibacterial
activity (
sum
better than individual agents)
Antagonism
Combination of antibiotics in which the activity of one or more
agent interferes with the activity of others (sum worse than
individual agents/inhibitory effect)
Antimicrobial agents can be
directly toxic
Life
-
threatening blood dyscrasia occurs in 1 in 60,000 individuals who
receive
chloramphenicol
-
no longer used. 1/60000 doesn’t seem too high
but it is when we now have better options
Damage to the kidneys can follow the use of aminoglycosides
.
Antimicrobial agents can interact with other drugs to
increase their toxicity
Antimicrobial agents can
alter microbial flora
Can cause what’s called antibiotic induced interpolitis (sp?) by altering
the gastrointestinal flora(killing all of the other natural flora), almost
all antibiotics can cause overgrowth of
Clostridium difficile
, which
produces a toxin that causes diarrhea and even pseudomembranous
colitis.
Alteration of intestinal flora by antibiotics can also result in overgrowth
of
Candida
in the mouth, vagina, or gastrointestinal tract
Allergic reactions
can be caused by antimicrobial agents
Penicillins can produce either immediate, IgE
-
mediated, or delayed
hypersensitivity reactions
Antibiotics must work with the immune system
.
Antibacterial agents are not capable of completely
eliminating an infection in a host with an extremely
compromised immune systems
Reasons:
Antibiotics can not reach all sites in the body
Antibiotics only kill or inhibit sensitive organisms
How does it happen? We do it…
Selection for resistant strains by giving antibiotics
Microbial adaptation and change
Treatment failure and emergence of diseases
Why should we care?
Are we creating “superbugs”? Untreatable infections
How can we stop (or at least slow) it?
Proper use of an antibiotics
Education of the healthcare provider and the patient
Mechanisms by which bacteria can “exchange” DNA
–
Horizontal
transfer.
It’ll receive foreign DNA to gain resistance via:
Transformation
cells take up DNA
Conjugation
mating through specialized appendages
requires cell to cell contact
Transduction
bacteriophage mediated
Types of mobile elements (ie Vectors)
Transposons
IS elements
Plasmids
Conjugative plasmids
Phage
Conjugaive Transposons
Pathogenicity Islands
Integrating Conjugative Elements (ICEs) and other mobilizable elements
Antibiotic resistance
Appropriate antimicrobial drug use is defined as use that maximizes therapeutic impact
while minimizing toxicity and the development of resistance.
Antibiotic resistance emerges when drugs are prescribed inappropriately
Infections caused by viruses. Ex. Ear infections in kids
–
most are caused by
viruses. Doctor prescribes antibiotics (not really targeting the exact cause…and
the kid gets better…bc they’ll always get better while the antibiotics didn’t do
anything)
Infections caused by bacteria not susceptible to the antibiotic
–
this is why we’re
discouraged from blind spectrums antibiotics
Antibiotics used at the wrong dose (mostly too low). If used at wrong dose, you
can induce resistance.
Section for bacteria resistance to the antibiotic
Selection for spread of resistance markers among bacteria
Example she likes to use: you’re actually selecting for resistance for the commensals in a person when you do this
and so what you can create is a person who can never be treated for tetracyline (for example) bc their
commensals become resistant so that every infection they get, those commensals are able to transfer that
resistance to whatever the bacteria is now causing the infection
Appropriate antimicrobial drug use should not be interpreted simply as reduced use
because these drugs offer valuable benefits when used appropriately.
1000
5
1000
100
1
1005
0.49
Sick
901
10
1000
100
2
911
1.09
Sick
704
19
1000
100
3
723
2.62
Better
311
35
1000
100
4
346
10.11
Healthy
0
60
1000
100
5
60
100
Healthy
0
0
1000
100
6
0
100
Healthy
0
0
1000
100
7
0
100
Healthy
0
0
0
100
8
0
100
Cured
Sensitive
Resistant
Killed by
Antibiotic
Killed by
Immune
System
Total
Bacteria
Day
Symptoms
Resistant
killed by
immune
system
1000
5
1000
100
1
1005
0.49
sick
900
10
1000
100
2
911
1.09
sick
704
19
1000
100
3
723
2.62
better
311
35
0
100
4
348
10.05
healthy
544
60
0
100
5
604
9.93
better
1012
110
1000
100
6
1122
9.80
sick
947
210
1000
100
7
1157
18.15
sick
799
402
1000
100
8
1201
33.47
sick
530
771
1000
100
9
1301
59.26
sick
19
1483
1000
100
10
1502
98.73
sick
0
2867
1000
100
11
2867
100
very sick
0
5634
1000
100
12
5634
100
very sick
Sensitive
Resistant
Killed by
Antibiotic
Killed by
Immune
System
Total
Bacteria
Day
Symptoms
Resistant
killed by
immune
system
Antibiotics are not a silver bullet
Antibiotics do not cure all infections
Most infections will resolve without antibiotic
treatment
–
like common cold
Proper dosage, patient understanding and
adherence to the treatment regiment is essential
Antibiotics are extremely valuable in the treatment
of bacterial infections but must be used properly
ensure that resistance is not induced
Appropriate antimicrobial drug use is defined as use
that maximizes therapeutic impact while minimizing
toxicity and the development of resistance.
Appropriate antimicrobial drug use should not be
interpreted simply as reduced use because these drugs
offer valuable benefits when used appropriately.
Inhibition of Cell Wall Synthesis
Disruption of Membranes
Inhibition of Nucleic Acid Synthesis
Inhibition of Protein Synthesis
Antimetabolites
Mechanism of action
Uses (spectrum)
Mechanisms of resistance
Inhibition of Cell Wall Synthesis
b
-
lactam antibiotics
Penicillins
Cephalosporins
Carbapenems and monbactams
Fosfomycin, Cycloserine and Bacitracin
Glycopeptides
Vancomycin
–
only talking about this one in particular
Antimycobacterial agents
Isoniazid
–
only talking about this one as well…there are other
antimycobacterial agents…but this one only targets antimycobacterial
agents
Disruption of Membranes
Polymyxins
Phase 1
In cytoplasm
Phase 2
At the membrane
Phase 3
Outside the cell
Phase 1:
soluble substrates
are activated and assembly
and transport inside the cells
Phase 2:
activated units are
attached and assembled on
the undecaprecol phosphate
membrane pivot at the
membrane.
Phase 3:
The peptidoglycan
units are attached to and
cross
-
linked into the
pepetidoglycan
polysaccharide outside the
cells
Fosfomycin
Cycloserine
b
-
Lactam
Review of Cell Wall Synthesis
Slide courtesy of Dr. Ru
-
ching Hsia
Vancomycin
Bacitrancin
Drugs that inhibit polymerization and attachment
of new peptidoglycan to cell wall
Penicillins
Cephalosporins
Carbapenems and monbactams
Drugs that inhibit biosynthetic enzymes
Fosfomycin and Cycloserine
Drugs that combine with carrier molecules
Bacitracin
Drugs that combine with cell wall substrates
Vancomycin
Slide courtesy of Dr. Ru
-
Ching Hsia
The last step of cell wall synthesis involves polymerization of
peptidoglycan subunits
This is the step of cell wall synthesis inhibited by ß
-
lactam antibiotics
Most ß
-
lactam antibiotics are bactericidal more so than static
ß
-
lactam antibiotics contain a four
-
membered ring, which
undergoes an acylation reaction with the transpeptidases that
cross
-
link the peptidoglycan polymers
–
not really responsible for structure
but wanted to mention is bc some broad/narrow spectrum are involved with this ring
The enzymes involved in this final process of cell wall formation
are called
penicillin
-
binding proteins (PBPs
) since they were
discovered by labeling with radioactive penicillin G.
The enzymes are different in Gram
-
positive and Gram
-
negative bacteria and
in anaerobic species.
Differences in the penicillin
-
binding proteins are responsible, to some
extent, for the differences in spectrums of the ß
-
lactam antibiotics.
Antibiotics
Spectrum of Activity
Natural penicillins: benzylpenicillin
(penicillin G), phenoxymethyl
penicillin (penicillin V)
Active against all β
-
hemolytic streptococci and
most other species; limited activity against
staphylococci; active against
meningococci
and
most gram
-
positive anaerobes; poor activity
against aerobic and anaerobic gram
-
negative
rods
Penicillinase
-
resistant penicillins:
methicillin, nafcillin, oxacillin,
cloxacillin, dicloxacillin
Similar to the natural penicillins, except
enhanced activity against staphylococci
Broad
-
spectrum penicillins:
aminopenicillins (ampicillin,
amoxicillin, carbenicillin, ticarcillin);
ureidopenicillins (piperacillin)
Activity against gram
-
positive cocci equivalent to
the natural penicillins; active against some gram
-
negative rods with piperacillin the most active
β
-
Lactam with β
-
lactamase inhibitor
(ampicillin
-
sulbactam, amoxicillin
-
clavulanate, ticarcillin
-
clavulanate,
piperacillin
-
tazobactam)
Activity similar to natural β
-
lactams, plus
improved activity against β
-
lactamase producing
staphylococci and selected gram
-
negative rods;
not all β
-
lactamases are inhibited;
piperacillin/tazobactam is the most active
Cephalosporins are
b
-
lactam antibiotics where
the
b
-
lactam ring is fused
with a dihydrothiazine
ring.
Cephamycins are related
to Cephalosporins but are
more resistant to
b
-
lactamases
Both have a
wider
antibacterial spectrum
,
resistance to many
b
-
lactamases and have
longer half
-
lifes improved
pharmacokinetic
properties over penicillins
Carbapenems
Broad spectrum
Resistance has been reported in oxacillin
-
resistant
staphylococci and
Pseudomonas
Monobactams
Narrow spectrum
Effective only against aerobic Gram negative bacteria
Three general mechanisms for resistance to
b
-
lactam
antibiotics
Prevention of the interaction between the
PBP
and the
antibiotic
Only occurs in Gram negative species where changes in porins
result in exclusion of the antibiotic
–
bc of the outer membrane, we
can’t get to target
Modification of the interaction between the
PBP
and the
antibiotic
Overproduction of the PBP
Acquisition of a new PBP
Modification of an existing PBP
Hydrolysis of the antibiotic by
b
-
lactamases
More than 200 different
b
-
lactamases have been described
Classes A
-
D
Some are specific of particular
b
-
lactam antibiotics while others have
broad spectrum activity against several kinds of
b
-
lactam antibiotics
Mechanism of action
inhibit polymerization and attachment of peptidoglycan
to cell wall (phase 3)
Uses (spectrum)
Range from narrow to broad depending on the particular
compound
Mechanisms of resistance
Exclusion from the target
PBP
Modification of the
PBP
b
-
lactamases
Inhibition of Cell Wall Synthesis
b
-
lactam antibiotics
Penicillins
Cephalosporins
Carbapenems and monbactams
Fosfomycin, Cycloserine and Bacitracin
Glycopeptides
Vancomycin
Antimycobacterial agents
Isoniazid
Cycloserine
Disruption of Membranes
Polymyxins
Fosfomycin and Cycloserine
Fosfomycin inhibits the enzyme UDP
-
GIcNAc
-
3
-
enol
-
pyruvyltransferase that is involved in the
first phase
of cell wall synthesis
Cycloserine is an inhibitor of both alanine racemase
and D
-
alanyl
-
D
-
alanine synthetase preventing the
cross
-
linkage of peptidoglycan that occurs in the
first
phase
of cell wall synthesis
Cycloserine is fairly toxic and is generally only used as a
secondary treatment for tuberculosis
Bacitracin
–
Bacitracin is a peptide antibiotic that specifically
interacts with the pyrophosphate derivate of the
undecaprenyl alcohol, preventing further transfer of the
muramylpentapeptide from the precursor nucleotide to
the nascent peptidoglycan
This occurs in
Phase II
of Cell Wall Synthesis
Vancomycin is a
glycopeptide.
Vancomycin binds to the
pentapeptide terminus and
inhibits both
transglycosylation and
transpeptidation reactions
during peptidoglycan
assembly
This occurs during
phase II
of cell wall synthesis
Vancomycin
Vancomycin is not effective against Gram
-
negative
bacteria
Because of its large size it can not penetrate the Gram
-
negative outer membrane
Vancomycin is used to treat Gram
-
positive
infections caused by organisms that are resistant
to
b
-
lactams
Vancomycin resistance is mediated by changes in
the pentapeptide terminus (the end where
vancomycin would bind to)
Vancomycin resistance can be encoded on mobile
genetic elements and can be transferred from one
species to another. (in commensals and they are
handing it off…esp in hospitals)
Phase 1
In cytoplasm
Phase 2
At the membrane
Phase 3
Outside the cell
Phase 1:
soluble substrates
are activated and assembly
and transport inside the cells
Phase 2:
activated units are
attached and assembled on
the undecaprecol phosphate
membrane pivot at the
membrane.
Phase 3:
The peptidoglycan
units are attached to and
cross
-
linked into the
pepetidoglycan
polysaccharide outside the
cells
Fosfomycin
Cycloserine
b
-
Lactam
Review of Cell Wall Synthesis
Slide courtesy of Dr. Ru
-
ching Hsia
Vancomycin
Bacitrancin
Isoniazid is bactericidal against actively replicating
Mycobacteria
Isoniazid inhibits synthesis of mycolic acid
–
which is
why isoniazid is specific for mycobacteria…other
bacteria do not produce mycolic acid
The precise mechanism by which isoniazid acts is not
known
Resistance to isoniazid results both from decreased
uptake of the drug into the cells and by alteration of
the enzymes involved in mycolic acid synthesis
Don’t get it confused…other drugs can work against
mycobacteria…it’s just that isoniazid will work only on
mycobacteria (ie. Useless against e.coli)
Fosfomycin and Cycloserine inhibit the first phase
of cell wall synthesis
Bacitracin inhibits the second phase of cell wall
synthesis
Vancomycin inhibits the second phase of cell wall
synthesis
It is not active against Gram negative bacteria
Resistance is caused by a change of the target enzyme
Isoniazid inhibits synthesis of mycolic acids
Used to treat infections caused by
Mycobacterium
Polymyxins
polymyxin B and colistin (polymyxin E)
high
-
molecular
-
weight octapeptides that inhibit Gram
-
negative bacteria
Not active against Gram positive bacteria
–
no outer membrane
Interact with the membrane and cause increased cell
permeability therefore cell death
Only used topically
-
bind to various ligands in body tissues
and are potent toxins for the kidney and nervous system
(seen in stuff like neosporin)
Inhibition of DNA Replication
Quinolones
–
some of the most widely used currently (new class so less
resistance for now…)
Nalidixic acid, ciprofloxacin, gatiflozacin
DNA damaging agents
Nitroimidazoles
Metronidazole
Inhibition of Transcription
(rather than damaging DNA)
Rifamycins
One of the most widely used class of antibiotics
Synthetic
agents that inhibit gyrase (bacterial topoII) or
topoisomerase IV thereby interfering with DNA
replication, recombination and repair
In Gram negative bacteria gyrase is usually the primary target
In Gram positive bacteria topoIV is usually the primary target
Bactericidal
Nalidixic acid was used to treat urinary tract
infections caused by Gram negative bacteria but
resistance to the drug developed rapidly
–
only
against gyrase
Newer fluoroquinolones such as Ciproflaxacin,
have broader spectrum against both Gram positive
and Gram negative bacteria
–
against both gyrase
and topoIV
Only
inhibits
anaerobic bacteria
and
protozoa
Nitroimidazols are reduced by an electron transport
protein in anaerobic bacteria. The reduced drug causes
strand breaks in the DNA.
(
They have to be converted to
an active form inside the bacteria. In aerobic…doesn’t
happen bc there’s no reduction)
Mammalian cells and aerobic bacteria (including facultative
bacteria) are unharmed because they lack enzymes to reduce the
nitro group of these agents.
Metroniadazole is one of the most commonly used
nitroimidazols
Bactericidal
Lots of anaerobic bacteria species in the oral cavity
(dentists use them)
Rifamycins (Rifampin, Rifabutin) bind to bacterial RNA
polymerase and inhibit initiation of RNA synthesis
Rifampin is bactericidal for
M. tuberculosis
and active against
many Gram positive bacteria
Gram negative bacteria are intrinsically resistant to rifamycins
because of decreased uptake of the drug
The outer membrane inhibits uptake of this hydrophobic antibiotic
Resistance develops quickly and is the result of a change in the
target
A chromosomal mutation in the gene encoding RNA polymerase
Quinolones
Inhibit gyrase and topoIV
Bactericidal
Widely used new agents have broad spectrum
Nitroimidazoles / Metroniadazole
Inhibits anaerobic bacteria
Bactericidal
Rifamycins
Inhibit bacterial RNA polymerase
Bactericidal
Resistance develops rapidly
Not effective against Gram negative bacteria
Inhibitors of 30S ribosomal subunit components
Aminoglycosides
Streptomycin, kanamycin neomycin, tobramycin, gentamicin,
amikacin
Tetracycines
Tetracycline, doxycycline, minocycline
Inhibitors of the 50S ribosomal subunit
Oxazolidinones and Lincosamde antibiotics
Linezolid
Clindamycin
Chloramphenicol
Macrolides
Erythromycin, Azithromycin, Clarithromycin
Streptogramins
Two
-
components group A and B
Quinupristin
-
dalfopristin (Synercid)
3
1
2
Oxazolindinones
4
5
3
Streptogramins
6
Bactericidal
-
Irreversibly bind to the 30S ribosome
Freeze the 30S initiation complex (30S
-
mRNA
-
tRNA) so that no
further initiation can occur.
Slow down protein synthesis that has already initiated and induce
misreading of the mRNA
Kanamycin, tobramycin, gentamicin
Effective against many Gram
-
negative and some Gram
-
positive bacteria (broad spec)
not useful for anaerobic (oxygen required for uptake of antibiotic) or
intracellular bacteria
Commonly used to treat infections caused by Gram negative rods
Synergize with
b
-
lactam antibiotics
b
-
lactams inhibit cell wall synthesis and thereby increase the uptake
of the aminoglycosides (no wall = easier to entry)
Mutation of the ribosomal binding site
Not common bc to prevent binding requires multiple
mutations
Decreased uptake of the antibiotic
Seen in
Pseudomonas
and anaerobic bacteria
Increased expulsion of the antibiotic (efflux)
Rare
only occurs in Gram negative bacteria
Enzymatic modification of the antibiotic
Most common form of resistance
Actually adding a component to the drug to make it inactive
Phosphotransferases
Adenyltransferases
Acetyltransferases
Bacteriostatic
–
Reversibly bind to the 30S
ribosomal subunit
Block binding of aminoacyl
-
transfer RNA (tRNA)
–
thus
very specific function (binding rt where t
-
RNA should
bind)
Broad Spectrum
Used to treat a wide variety of infections caused by:
Chlamydia
Mycoplasma
Rickettsia
And a variety of other Gram positive and Gram negative bacteria
Tetracycline, Doxycycline, Minocycline
Decreased uptake of the antibiotic
Active efflux of the antibiotic
Most common cause of resistance in Gram negative
bacteria by pumping the actual drug out
Alteration of the ribosomal target
Enzymatic modification of the antibiotic
3
1
2
Oxazolindinones
4
5
3
Streptogramins
6
Linezolid most commonly used
Bind the 50S ribosomal subunit
Distorts the binding site for the tRNA and inhibits
formation of the 70S initiation complex
Narrow spectrum
Unique mechanism of action so cross resistance with
other protein inhibitors does not occur
Most commonly used against drug resistant enterococci
Active against Gram positive cocci
Including those resistant to penicillins, vancomycin and
aminoglycosides
Lincomycin and its derivative Clindamycin
Block protein elongation by binding to the 50S subunit of
the ribosome
Spectrum
–
“relatively broad”
Staphylococci and anaerobic Gram
-
negative rods
Not active against most aerobic Gram negative bacteria
Resistance
Methylation of the 23S RNA
Enzymatic inactivation of the antibiotic
Cross
-
resistance occurs with macrolides since alteration of
23S will affect other drugs
Inhibitors of 30S ribosomal subunit components
Aminoglycosides
Streptomycin, kanamycin neomycin, tobramycin, gentamicin,
amikacin
Tetracycines
Tetracycline, doxycycline, minocycline
Inhibitors of the 50S ribosomal subunit
Oxazolidinones and Lincosamde antibiotics
Linezolid
Clindamycin
Chloramphenicol
Macrolides
Erythromycin, Azithromycin, Clarithromycin
Streptogramins
Two
-
components group A and B
Quinupristin
-
dalfopristin (Synercid)
Bacteriostatic
Binds reversibly to the 50S ribosomal subunit
Broad Spectrum
Similar spectrum to tetracycline
Not commonly used in the US because it can disrupt
protein synthesis in human bone marrow and cause
aplastic anemia (1 in 60,000 patients)
Resistance
Enzymatic inactivation of the antibiotic (acetylation
than phosphorylation)
Changes in the outer membrane of Gram negative
bacteria to reduce uptake
Bacteriostatic
Binds reversibly to the 23S RNA component of the 50S
ribosomal subunit
Erythromycin, Azithromycin, Clarithromycin
Broad Spectrum
Primarily used to treat pulmonary/respiratory infections
caused by Gram+
Mycoplasma, Legionella and Chlamydia species
Most Gram negative bacteria are resistant
(true in that the
level of drug required to combat these are way too high)
Resistance
Methylation of the 23S RNA
Enzymatic inactivation of the antibiotic
Other changes in the 23S RNA and proteins of the 50S
subunit
Cross
-
resistance occurs with Lincosamide antibiotics
3
1
2
Oxazolindinones
4
5
3
Streptogramins
6
Cyclic peptides
administered as a
combination
of
two components
Group A and Group B Streptogramins
The two components act synergistically
The Group A component binds to the 50S ribosomal
subunit and facilitates binding of the Group B
component
The Group B component inhibits chain elongation
Both components NEEDS to work together
The most commonly used Steptogramin is
quinupristin
-
dalfopristin
Spectrum
Most commonly used against staphylococci, streptococci
and
Enterococcus faecium
.
-
primarily against
vancomycin resistant
E. faecium
3
1
2
Oxazolindinones
4
5
3
Streptogramins
6
Inhibition of Cell Wall Synthesis
Disruption of Membranes
Inhibition of Nucleic Acid Synthesis
Inhibition of Protein Synthesis
Antimetabolites
Interference with folate metabolism
Sulfonamides
Inhibitors of pteroic acid synthetase
Trimethoprims
Inhibitors of dihydrofolate reductase
Most bacteria cannot use pre
-
formed folic acid and must synthesize
folic acid
–
which makes it a key target
Exception: Enterococci can use exogenous thymidine and are
intrinsically resistant inhibitors of this process
In contrast, Human cannot synthesize folic acid and must obtain it
from food consumption so inhibition of folic acid synthesis won’t
negatively affect us
Folic acid is synthesized by joining three components together
Enterococci can use exogenous thymidine and are intrinsically resistant
inhibitors of this process
Sulfonamides
Inhibitors of pteroic acid synthetase
bacteriostatic
Trimethoprims
Inhibitors of dihydrofolate reductase
bacteriostatic
Both are broad range
Used against a variety of Gram positive and Gram
negative bacteria (except enterococci)
Sulfonamides and Trimethoprims are
commonly used together
Synergistic since they act at diff steps of a process
Ex) Dapsone and p
-
aminosalicylic acid
Resistance
Stems from a variety of mechanisms
Permeability barriers
Decreased affinity of dihydrofolate reductase for
trimethoprim by changing enzyme activity
Enterococci can use exogenous thymidine and are
intrinsically resistant
Inhibition of Cell Wall Synthesis
Disruption of Membranes
Inhibition of Nucleic Acid Synthesis
Inhibition of Protein Synthesis
Antimetabolites
Mechanism of action
Uses (spectrum)
Mechanisms of resistance
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