Download Antimicrobial drugs

Chapter 10
Controlling microbial growth in the
body: Antimicrobials
• Like disinfectants antimicrobial drugs act by
killing or inhibiting the growth of
microorganisms.
• Antimicrobial drugs must act within the body
and show _______________________.
Antimicrobial Drugs
• Chemotherapy: the use of drugs to treat a
disease
• Antimicrobial drugs: interfere with the growth of
microbes within a host
• Selective toxicity: killing harmful microbes
without damaging the host
Representative Sources of Antibiotics
Insert Table 20.1
Spectrum of Activity
• ________________: Antibiotic affects a large
number of Gram-positive or Gram-negative
bacteria
• ________________: Affective against a small
range of organisms
– Penicillin G affects Gram-positive bacteria but very
few Gram-negatives
The Spectrum of Activity of Antibiotics and Other Antimicrobial Drugs
Spectrum of Activity
– Use of broad spectrum drugs also destroy ______
_______________
– Survivors may become _______________
– Yeast infections may arise from the over growth of
Candida albicans
• _______________
– Term is also applied to growth of a target pathogen that has
developed resistance to the antibiotic
– Antibiotic resistant strain replaces the original sensitive strain
and the infection continues
• Antibiotics are only effective against ________
infections
• ________(flu) and ______________are _____
infections therefore antibiotics are ineffective!
Inhibition of Cell Wall Synthesis
–
• Most common agents prevent cross-linkage of NAM
subunits
• Beta-lactams are most prominent in this group
– Functional groups are beta-lactam rings
– Beta-lactams bind to enzymes that cross-link NAM
subunits
• Bacteria have weakened cell walls and eventually lyse
Inhibition or degrading bacterial cell walls.
N-acetylglucosamine (NAG)
N-acetylmuramic acid (NAM)
Side-chain amino acid
Cross-bridge amino acid
Tetrapeptide side chain
Peptide cross-bridge
NAM
Peptide
bond
Carbohydrate
“backbone”
Structure of peptidoglycan in
gram-positive bacteria
.
Inhibition or degrading bacterial cell
walls.
• Penicillin's
• Cephalosporin's
• Vancomycin
The inhibition of bacterial cell synthesis by penicillin.
Rod-shaped bacterium before
penicillin.
The bacterial cell lysing as penicillin
weakens the cell wall.
• One of the most successful groups of
antibiotics targets the synthesis of bacterial
cell walls; why does the antibiotic not affect
the mammalian cell?
The inhibition of protein synthesis by antibiotics.
Protein
synthesis
site
Growing
polypeptide
Tunnel
Growing polypeptide
50S
5′
Chloramphenicol
Binds to 50S portion and
inhibits formation of peptide
bond
30S
mRNA
50S
portion
3′
Three-dimensional detail of the protein
synthesis site showing the 30S and 50S subunit
portions of the 70S prokaryotic ribosome
Protein synthesis site
tRNA
Messenger
RNA
Streptomycin
Changes shape of 30S portion,
causing code on mRNA to be
read incorrectly
30S portion
70S prokaryotic
ribosome
Translation
Direction of ribosome movement
Tetracyclines
Interfere with attachment of
tRNA to mRNA–ribosome
complex
Diagram indicating the different points at which chloramphenicol, the
tetracyclines, and streptomycin exert their activities
Inhibitors of Protein Synthesis
– Prokaryotic ribosomes are 70S (30S and 50S)
– Eukaryotic ribosomes are 80S (40S and 60S)
– Drugs can selectively target translation
– Mitochondria of animals and humans contain 70S
ribosomes
• Can be harmful
Inhibitors of Protein Synthesis
• Chloramphenicol
– Broad spectrum
• Binds 50S subunit; inhibits peptide bond formation
Inhibitors of Protein Synthesis
• Aminoglycosides
– Streptomycin
• Broad spectrum
– Change shape of 30S subunit
• Can have fatally toxic effects on Kidneys
Inhibitors of Protein Synthesis
• Tetracyclines
– Broad spectrum
• Interfere with tRNA attachment
– Side effects? Should Children take tetracycline?
• Children may experience a brown discoloration of teeth
• Pregnant women may cause liver damage
– Most common antibiotic added to animal feed
• Use results in significantly faster weight gain
Inhibition of nucleic acid replication and transcription
Inhibitors of Nucleic Acid Synthesis
– Several drugs block DNA replication or mRNA
transcription
– Drugs often affect both eukaryotic and prokaryotic
cells
– Not normally used to treat infections
– Used in research and perhaps to slow cancer cell
replication
Inhibitors of Nucleic Acid Synthesis
• Rifamycin
– Inhibits RNA synthesis
– Antituberculosis
Injury to the plasma membrane of a yeast cell caused by an antifungal drug.
Injury to the Plasma Membrane
• Some drugs form channel through cytoplasmic
membrane and damage its integrity
• Polymyxin B
– Topical
– Combined with bacitracin and neomycin in
over-the-counter preparation
Inhibiting the Synthesis of Essential
Metabolites: Antimetabolics
– Antimetabolic agents can be effective when
metabolic processes of pathogen and host
differ
– Sulfonamides (sulfa drugs)
 Inhibit folic acid synthesis
 Broad spectrum
Inhibiting the Synthesis of Essential Metabolites: Antimetabolics
Figure 5.7bc Enzyme inhibitors.
Action of Enzyme Inhibitors
Competitive
inhibitor
Altered
active site
Noncompetitive
inhibitor
Allosteric
site
Major Action Modes of Antimicrobial Drugs.
1. Inhibition of cell wall synthesis: penicillins,
2. Inhibition of protein synthesis: chloramphenicol,
cephalosporins, bacitracin, vancomycin
erythryomycin, tetracyclines, streptomycin
DNA
mRNA
Transcription
Protein
Translation
Replication
Enzyme
4. Injury to plasma
membrane:
polymyxin B
5. Inhibition of essential
metabolite synthesis:
sulfanimide, trimethoprim
3. Inhibition of nucleic acid replication
and transcription: quinolones, rifampin
Clinical Considerations in Prescribing Antimicrobial Drugs
• Routes of Administration
– Topical application of drug for external infections
– Oral route requires no needles and is selfadministered
– Intramuscular administration delivers drug via
needle into muscle
– Intravenous administration delivers drug directly to
bloodstream
Figure 10.13 The effect of route of administration on blood levels of a chemotherapeutic agent
Administration method
Relative concentration of drug in blood
Oral
Intramuscular
(IM)
Continuous
intravenous
(IV)
Time (hours)
Clinical Considerations in Prescribing Antimicrobial Drugs
• Safety and Side Effects
– Toxicity
• Cause of many adverse reactions poorly understood
• Drugs may be toxic to kidneys, liver, or nerves
• Consideration needed when prescribing drugs to
pregnant women
– Allergies
• Allergic reactions are rare but may be life threatening
• Anaphylactic shock
Figure 10.14 Some side effects resulting from toxicity of antimicrobial agents-overview
Black hairy tongue caused by
antiprotozoan drug
metronidazole (Flagyl)
Temporary and Harmless!
Discoloration and damage to tooth enamel
caused by tetracycline
Resistance to Antimicrobial Drugs
• The Development of Resistance in
Populations
• Some pathogens are naturally resistant
• Resistance by bacteria acquired in two
ways
• New mutations of chromosomal genes
• Acquisition of R-plasmids via
transformation, transduction, and
conjugation
Antibiotic Resistance
• Misuse of antibiotics selects for resistance
mutants
• Misuse includes:
–
–
–
–
–
Resistance
plasmid
S. enterica
after conjugation
S. enterica
Cephalosporin-resistance in E. coli
transferred by conjugation to
Salmonella enterica in the intestinal
tracts of turkeys.
E. coli
Clinical Focus Antibiotics in Animal Feed Linked to Human Disease, Figure A.
Antibiotic Resistance
– At least 6 mechanisms of microbial resistance
1.
2.
3.
4.
5.
6.
Effects of Combinations of Drugs
• __________occurs when the effect of two
drugs together is greater than the effect of
either alone
• ___________occurs when the effect of two
drugs together is less than the effect of either
alone
Figure 20.23 An example of synergism between two different antibiotics.
Area of synergistic
inhibition, clear
Disk with antibiotic
amoxicillin-clavulanic
acid
Area of growth,
cloudy
Disk with antibiotic
aztreonam