Antimicrobial Drugs
Chapter 20
History of Chemotherapy
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Chemotherapy
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Antimicrobial
drugs
Selective
toxicity
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Alexander
Fleming (1929)
Penicillin
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Antibiotic
Produced by
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Molds
Penicillium
and Cephalosporium
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Bacteria
Streptomyces
and Bacillus
Spectrum of Antimicrobial Activity
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Broad spectrum
vs. narrow spectrum
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Tetracyline
vs. penicillin
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Disadvantage
of broad spectrum
Superinfection
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Ex. Candida albicans
Major Modes of Action
(Fig 20.2)
Antimicrobial Action
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Inhibition of
peptidoglycan synthesis
No peptidoglycan
Weak cell wall
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Cell lysis
Only actively growing
cells
Selectively toxic
Example:
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Penicillin
Antimicrobial Action
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Inhibition of
protein synthesis
Selective
toxicityΰdifference
in ribosomes
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Bacteria= 70S
ribosome (50S and 30S portions)
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Ribosomes are
key players in protein synthesis
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Chloramphenicol (bacteriostatic and broad spectrum)
50S portion
Inhibits formation of peptide
bonds
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Tetracycline
(bacteriostatic and broad spectrum)
30S portion
Interference with attachment of
tRNA, which carries aa
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Streptomycin
(bacteriocidal and broad spectrum)
30S portion
Changes shape of 30S portion and
genetic code read wrong
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Erythromycin
(bacteriostatic and Gram + only)
50S portion
Prevents translocation
Antimicrobial Action
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Injury to
plasma membrane
Changes cell
permeability
Loss of
metabolites or cell bursting
EX) polymyxin
B (Neosporin) attaches to phospholipids (bacteriocidal and Gram neg.)
EX)
amphotericin B combines with sterols in fungal membranes (Fungicidal)
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Targets
ergosterola sterol specific to fungi
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Can be toxic
to kidney cells of humans, however
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Administered
in liposomes
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Inhibition of
nucleic acid synthesis
More difficult
to find b/c of lack of selective toxicity
EX) Rifampin
inhibits mRNA synthesis (bacteriocidal and Mycobacterium tuberculosis)
Antimicrobial Action
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Inhibition of
synthesis of essential metabolites
Essential enzymes are
competitively inhibited
EX)sulfanilamide
(bacteriostatic and broad spectrum)
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Microbes
normally produce folic acid from a para-aminobenzoic acid (PABA) substrate and
an enzyme
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When
sulfanilamide is present the enzyme binds to it instead
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Humans get
folic acid from food
Mechanisms of Drug Resistance
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Destruction or
inactivation of antibiotic
Production of
an acid perhaps
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Some organisms
can prevent some drugs from penetrating them
Gram
negatives have this ability with some antibiotics
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Alteration of
target site
Some cells can
alter their structures so antibiotics wont work on them
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Rapid efflux
Some cells
have systems for pumping the antibiotic back out of the cell
Resistance
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Resistance is
usually hereditary
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Can also be
passed via horizontal gene transfer
Plasmids* and
conjugation
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Replacement of
sensitive bacteria in a population by resistant bacteria*
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Misuse of
antibiotics can lead to increased resistance
Lack of
prescriptions
Improper use
(headaches and viruses)
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CDC estimates
percentage of wrong prescriptions
30% ear infections, 50% sore throats,
100% colds
Weak forms
select for resistant bacteria
Not taken long
enough
Use to promote
animal growth
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Animal feed
supplements
Drug Combinations
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In case the
organism is resistant to one drug why not use two at same time
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Synergism:
drug assistance
EX) penicillin
and Streptomycin for bacterial endocarditis
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Penicillin
disrupts cell wall and Streptomycin gets in faster
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Antagonism:
One drug makes other ineffective
EX) penicillin
and Tetracycline
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Tet interferes
with Penicillin
Chemotherapeutic Future
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Modify
existing drugs
Extend
spectrum
Prevent
resistance
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New targets of
activity
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Antibiotics
from plants or animals
EX)magainin
from frogs or cecropin from moths
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Triplex agents
DNA that will
selectively bind to site on DNA or mRNA where pathogenic protein is coded and
prevent the production of the pathogenic protein
Prevent
production rather than destroy product
Problem with
penetration