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Antimicrobial
Agents
Use when balance tips in
favor of invading MO
Antimicrobial Therapy
When balance between MO and host
tilts in direction of MO, body’s
normal defense cannot prevent or
overcome disease
Turn to Chemotherapy - treatment of
disease with chemical drugs into body
Chemotherapeutic
Agents
Antimicrobial - to treat infectious
disease, act within host
Antibiotic - produced naturally by MO
(bacteria, fungi)
Synthetic drug – synthesized, made in
laboratory
Successful Antimicrobial
Selective toxicity - harm MO not host
(all drugs have some side-effects)
No hypersensitivity reaction – does not
elicit harmful host immune reaction
Penetrate - gets to site of tissue
infection rapidly, retain for adequate
time
No resistance - MO not readily able to
counteract it
Activity of Antimicrobial
Easier to find against prokaryote as
different from eukaryotic cell
Fungi, protozoan, helminth are
eukaryotes; make finding drug with
selective toxicity more difficult
Especially difficult to find drug
against virus, require host cell to
replicate
Spectrum of Antibiotics
Narrow spectrum - affects relatively few
kinds of bacteria
Broad spectrum - effective against large
number Gram(+) & Gram(-) bacteria
Problem of broad spectrum antibiotic use
is NF destroyed, allow certain NF to
flourish and cause opportunistic infection
Superinfection - overgrowth of NF due to
antibiotic treatment for an initial
infection
Action of Antimicrobial
Bacteriocidal - kill bacteria
Bacteriostatic - prevent growth of
bacteria; host’s defense of phagocytosis
and antibody eliminate bacteria
Different areas in bacteria serve as
target for action of antimicrobial:
Cell wall
Ribosome
Plasma membrane
DNA, RNA
Metabolite
Bacterial Cell Wall Cross Linking
Interference with synthesis of bacterial cell
wall should not harm host
Bacterial cell wall contain peptidoglycan not
found in eukaryotic cell
Many antibiotics prevent synthesis of
peptidoglycan by interfering with linkage by
peptide cross-bridge
Inhibition of Bacteria Cell
Wall Biosynthesis: Lactam Ring
These antibiotics contain beta lactam
ring that bind to group of bacterial
enzymes called penicillin binding
proteins (PBP)
PBP involved in peptidoglycan cell wall
synthesis
Binding of PBP prevents peptide cross
linking, cell wall weakened, bacteria
undergoes lysis
Beta Lactam Ring Antibiotics
Affect cell wall synthesis, only
effective on actively growing MO
These antibiotics include:
Penicillin and derivatives (ampicillin,
methacillin, oxacillin, amoxacillin, augmentin)
Cephalosporin (cephalothin, cefuroxime,
ceftazidime, cefoxitin)
Carbapenem (imipenem)
Monobactam (aztrenam)
Inhibition of Bacterial Cell
Wall Biosynthesis: Others
Bacitracin - interferes with synthesis of
peptidoglycan by inhibiting recycling of
metabolites
Vancomycin - binds to precursors used in
cell wall synthesis; interfere with
enzymes that incorporate these
precursors into growing cell wall
Inhibition of mRNA
Translation
Protein synthesis common feature of all
cells
Ribosome structure of eukaryote and
prokaryote cell differ (80S vs 70S)
Many antimicrobials specifically
interfere with mRNA protein synthesis
on prokaryotic 70S ribosomes
Some antimicrobials act on 50S subunit
of the ribosome, while others act on
30S subunit of ribosome
Inhibition of Bacteria Translation
Chloramphenicol - acts
at 50S, inhibit
formation of peptide
bond
Erythromycin - acts at
50S, prevent
translocation
movement of ribosome
Tetracycline - acts at
30S, interfere with
tRNA attachment
Aminoglycosides
(gentamycin,
streptomycin) - act at
30S, cause misreading
of mRNA
Injury to Bacteria Plasma
Membrane
Polypeptide antimicrobials
Polymyxin B
Colistin
Affect permeability of cells
Result in leakage of macromolecules and
ions essential for cell survival
Inhibition of Bacteria
DNA/RNA Synthesis
Ciprofloxacin (fluoroquinolone) - bind
and interfere with DNA gyrase involved
in DNA supercoiling
Metronidazole - breaks DNA strand
Rifampin - binds to DNA dependentRNA polymerase to inhibit mRNA
synthesis
Inhibition Bacteria Folate Synthesis
Antimetabolite closely resemble
normal substrate
(analogue), competes
for enzyme
Both sulfonamide and
trimethoprim
interfere with folic
acid pathway
Often in single pill
used in combination
drug therapy:
TrimethoprimSulfamethoxazole
(TMP-SMX, Bactrim)
Broad spectrum
antimicrobial
Inhibition of Bacteria
Enzymatic Activity
Nitrofurantoin - targets synthesis of
several bacterial enzymes and proteins;
may also directly damage DNA
Isoniazid - structural analogue of
vitamin B6; inhibits synthesis of mycolic
acid of Mycobacteria cell wall
Ethambutol - inhibits incorporation of
mycolic acid into Mycobacteria cell wall
Summary: Bacteria Antimicrobial
Antifungal Drugs
Nystatin and amphotericin B combine with sterols
to disrupt fungal plasma membrane
Effective because animal sterols are mostly
cholesterol while fungal membranes contain mainly
ergosterol against which the drugs target
Ketoconazole (imadazole) - interfere with sterol
synthesis
Griseofulvin - binds to keratin on skin, hair, and
nails; interferes with mitosis and fungal
reproduction
Antiviral Drugs: Nucleoside
Analogue
In viral nucleic
acid, analogue
insert in place of
normal nucleoside
Nucleic acid
synthesis stops
Nucleoside
analogue binds
more strongly
with viral enzyme
than host cell
enzyme
Example:
acyclovir for
herpes virus; also
several
nucleoside
analogues for
HIV infection
Other Antiviral Drugs
Interferon – protein made by host cell for
first line of antiviral defense; cloned by
recombinant DNA technology, treatment for
severe and chronic virus infections
Tamiflu, Relenza – interfere with release of
influenza virus from host cell
Protease inhibitors – interfere with proteolytic
cleavage of HIV polyproteins into individual
proteins, stops replication process
Anti-sense or siRNA (small, interfering RNA) –
experimental antiviral drugs, inhibits mRNA
translation
Antimicrobial Susceptibility Testing
Important as different MO species and
strains have different degree of
susceptibility to different antimicrobials
Susceptibility of MO to antimicrobial may
change with time, even during course of
antimicrobial therapy
Drug Sensitivity Test:
Diffusion Test
• Kirby-Bauer Test –
standardized lab test with
antibiotic impregnated disk,
diffuses out in a concentration
gradient, measure zone of
inhibited bacterial growth
• E Test – utilizes plastic coated
strip containing gradient of
antibiotic that diffuses out,
allows estimate Minimal
Inhibitory concentration (MIC)
that prevents visible bacterial
growth
Drug Sensitivity Test:
Test Tube Dilution
• Broth Dilution Test – measures more
accurately serial antibiotic dilutions in
broth test tube for MIC, followed by
plating for Minimal Bacteriocidal
Concentration (MBC)
Antibiotic Resistance
Presently a common occurrence
Bacterial drug resistance requires
interruption or disturbance of the steps
for antimicrobial action
Antibiotic Resistance
Intrinsic resistance - normal genetic,
structural, or physiologic state of MO;
considered natural and inherited
characteristic associated with majority of
strains of bacterial group
Acquired resistance - altered cellular
physiology and structure caused by
changes in a MO genetic makeup; may be a
trait associated with only some strains of
bacterial group
Acquired Antibiotic
Resistance
Acquisition of genes from other MOs via
gene transfer mechanisms (i.e.,
resistance plasmids)
A combination of mutational and gene
transfer events
Pathways of Antibiotic
Resistance
Enzymatic Degradation:
Penicillinase
Resistance to penicillin and other
beta-lactam antibiotics
Production of an enzyme that breaks
beta-lactam ring
Gram(+) MO Resistance to Betalactam Antibiotics
Enzymatic
degradation – MO
produces betalactamase, cleaves
ring structure of
antibiotic
Altered
antimicrobial target
– MO mutation of
penicllin binding
proteins (PBP) so
antibiotic no longer
binds to it
Gram(-) Resistance to Beta-lactam
Antibiotics
Decrease uptake - of antibiotic
Enzymatic degradation – of antibiotic
Altered antimicrobial target - PBP
Dissemination of
Antimicrobial Resistance
Prevention of Bacterial
Antimicrobial Resistance
Use antimicrobial drugs only when
necessary
Finish prescribed course of antimicrobial
Use drugs in combination; microbe less
likely to develop resistance to two drugs
at the same time:
Consider synergistic effects
Consider antagonistic effects