Antimicrobial Drugs

Drugs, Microbes, Host – Elements of Chemotherapy

Ch 20
A Glimpse of History
Paul Ehrlich (1854–1915)
◦ Degree in medicine
◦ Observed some dyes stain bacterial but not animal cells
 Indicated fundamental difference between cell types

Searched for “magic bullet” that would kill microbial pathogens without
harming human host
Synthesized arsenic compounds to treat syphilis, caused by spirochete
Treponema pallidum
In 1910, the 606th tested compound proved effective in laboratory
animals
 Arsphenamine, named Salvarsan
 Potentially lethal for patients but did cure infections previously
considered hopeless
 Proved some chemicals could selectively kill microbes
Antibiotics
Antimicrobials vs antibiotics (sources)
Chemotherapy is treatment of disease
Desirable characteristics
◦ Specificity (target the pathogen)
◦ Few side effects (low toxicity)
◦ Narrow spectrum (leaves normal biota)
◦ Localization and stability in host
◦ Shelf life and cost are important too
Possible Adverse Reactions
Toxicity to organs
Allergies
Disruption of
normal flora
Other adverse
effects
General Concepts
Antibiotics: antibacterial agents
◦ Naturally occurring (Penicillin)
◦ Semi-synthetic: slight alterations to naturally occurring
agents
◦ Synthetics: synthesized
in the laboratory
General Concepts
Itis important that any antibiotic demonstrate
selective toxicity.
◦ The drug must be more toxic to a pathogen than a pathogen’s
host.

This selective toxicity is possible due to difference in

structure or metabolism between the pathogen and the
host.
Thought Questions
THOUGHT QUESTION A: Can you think of any difference
between a human host and a bacterial pathogen that would be
a target for antibacterial agents?

THOUGHT QUESTION B: Why are antibacterial drugs much

more common than antifungal, antiprotozoan, and
antihelmintic drugs?
Classification of Antimicrobial Drugs
1. Inhibition of cell wall
synthesis

2. Inhibition of protein
synthesis

3. Disrupt cytoplasmic
membrane

4. Inhibit metabolism

5. Inhibit DNA/RNA
synthesis

6. Block attachment
Classification of Antimicrobial Drugs
1. Inhibition of cell wall
synthesis

2. Inhibition of protein
synthesis

3. Disrupt cytoplasmic
membrane

4. Inhibit metabolism

5. Inhibit DNA/RNA
synthesis

6. Block attachment
Inhibition of Cell Wall Synthesis
Peptidoglycan: alternating NAM and NAG subunit
chains that are held together by peptide bridges
◦ When reproducing and growing, bacteria must
synthesize more NAG/NAM units to add.
 Beta()-lactams
 Prevent
cross-linkage of NAM subunits
◦ Example: Penicillin
Beta()-lactams
Cephalosporins (beta()-lactams)
 Prevent cross-linkage of NAM subunits
 More stable, more easily absorbed, work on some gram (-)
◦ Examples: methicillin and cephalosporin

EXAMPLES:
FIRST GENERATION:
Keflex
Duricef 
SECOND GENERATION:
Ceclor 
THIRD GENERATION:
Rocephin 
Other cell wall inhibitors
 Vancomycin: interfere with specific bridges that link
NAM subunits in Gram-positives.

 Bacitracin: blocks secretion of NAG and NAM from

cytoplasm of Gram-positives.

 Isoniazid: block mycolic acid addition to cell walls as

well as peptidoglycan production

THOUGHT QUESTION: Which bacterial genus would

be most effected by Isoniazid?
Thought questions
If a patient comes in with an infection of a
bacterium that is dormant, yet still causing
infection, would these classes of antibiotics
work?
Classification of Antimicrobial Drugs
1. Inhibition of cell wall
synthesis

2. Inhibition of protein
synthesis

3. Disrupt cytoplasmic
membrane

4. Inhibit metabolism

5. Inhibit DNA/RNA
synthesis

6. Block attachment
Inhibition of Protein Synthesis
Eukaryotic
 Ribosomes are the major structure of a
cell that caries out protein synthesis.

 Eukaryotic and prokaryotic ribosomes

differ in size and structure

THOUGHT QUESTION: Why is

the bacterial ribosome a good
target for antimicrobial drugs? Prokaryotic
Inhibition of Protein Synthesis
 There are two major subunits of the ribosome:
◦ 30S subunit
◦ 50S subunit
 Both a critical in reading codons and initiating protein
synthesis.
 The 50S also forms peptide bonds between amino acids.
Aminoglycosides
change the shape of the
30S subunit.
◦ Ex. streptomycin and
gentomycin
Aminoglycosides
prevent amino acids
from entering the
ribosome at the 30S
subunit.
◦ Ex. tetracycline
Chloramphenicol
blocks 50S ribosome, preventing peptide bond
formation.
Macrolides
Bind to 50S ribosome.
Prevent movement from one codon to the next, halting
translation
Ex. Erythromycin
Thought Question
On which bacteria, Gram-positive or
Gram-negative, would these antibiotics be
most effective?
Classification of Antimicrobial Drugs
1. Inhibition of cell wall
synthesis

2. Inhibition of protein
synthesis

3. Disrupt cytoplasmic
membrane

4. Inhibit metabolism

5. Inhibit DNA/RNA
synthesis

6. Block attachment
 Disruption of cytoplasmic membranes
 Plasma membranes are
phospholipid bi-layers that
contain sterols.
◦ Fungi contain a sterol called
ergosterol; human membranes
contain cholesterol
 Two anti-fungal drugs exploit this
fact:
◦ Polyenes attach to ergosterol in
the membrane. 1. CLOTRIMAZOLE
◦ Azoles inhibit ergosterol (LOTRIMIN®),
synthesis
2. MICONAZOLE
(MICATIN®),
3. FLUCONAZOLE
(DIFLUCAN®)
Disruption of cytoplasmic membranes
Polymyxin:
◦ disturbs phospholipid bi-layers

◦ Effective against Gram-negative

bacteria
 Ex. Pseudomonas

◦ toxic to kidneys and is usually used

for external pathogens
Classification of Antimicrobial Drugs
1. Inhibition of cell wall
synthesis

2. Inhibition of protein
synthesis

3. Disrupt cytoplasmic
membrane

4. Inhibit metabolism

5. Inhibit DNA/RNA
synthesis

6. Block attachment
Anti-Metabolic Agents
Metabolism: all of the chemical reactions
within a cell used to store or release energy.
◦ Organisms often have unique metabolic pathways.

THOUGHT QUESTION: Is Glycolysis and

the Krebs cycle a good target for these
classes of drugs?
Sulfonamides
 similar in structure to PABA, a chemical critical in the
synthesis of nucleotides for DNA and RNA synthesis.
 the presence of sulfonamides shuts down DNA/RNA
synthesis and, thus, protein synthesis.
Sulfonamides
Why is this an effective antibacterial agent?
◦ Humans derive folic acids from our diet and
convert them to THF.
Amantadine and Rimantadine
Block uncoating of viral particles by
neutralizing the pH within the lysosome.

Effective in fighting influenza type A virus.

Classification of Antimicrobial Drugs
1. Inhibition of cell wall
synthesis

2. Inhibition of protein
synthesis

3. Disrupt cytoplasmic
membrane

4. Inhibit metabolism

5. Inhibit DNA/RNA
synthesis

6. Block attachment
 Inhibition of Nucleic Acid Synthesis
 many compounds called nucleotide analogs mimic normal
nucleotides used to build DNA/RNA.
 these are incorporated into DNA and RNA and prevent
further replication, transcription, or translation.
◦ Commonly used to fight viral replication in Herpes and HIV.
 Ex. ACV and AZT
Inhibition of Nucleic Acid Synthesis
Quinolones attack DNA replication specifically by
attacking an enzyme associated with DNA uncoiling
(DNA gyrase).
◦ no effects on eukaryotes or viruses

EXAMPLES:
CIPROFLOXACIN (Cipro)
OFLOXACIN
NORFLOXACIN
Levoflaxin 3rd gen
Trovaflaxin
Inhibition of Nucleic Acid Synthesis
Rifampin: binds to bacterial RNA polymerase (enzyme
used in transcription).
◦ used to fight Mycobacterium tuberculosis
Classification of Antimicrobial Drugs
1. Inhibition of cell wall
synthesis

2. Inhibition of protein
synthesis

3. Disrupt cytoplasmic
membrane

4. Inhibit metabolism

5. Inhibit DNA/RNA
synthesis

6. Block attachment
Mode of Action
Prevention of Virus Attachment
Attachment analogs, typically sugar or
protein analogs, block viral attachment to a
host cell.

Arildone is one antagonist used to block

attachment of poliovirus and some common
cold viruses.
Mechanisms of drug action
Overview of the goal of chemotherapy
CLINICAL
CONSIDERATIONS
CLINICAL CONSIDERATIONS
1. Availability

2. Expense

3. Stability of Chemical

4. Non-toxic and non-allergenic

5. Selectively toxic against a wide range of

pathogens
Spectrum of Action
 Spectrum of Action: the number of different kinds of
pathogens a drug acts against.
◦ Narrow Spectrum and Broad-Spectrum Drugs
Spectrum of Antibiotics
Thought Question
What is the use of broad spectrum antibiotics
not always desirable? (Hint: think of the role
of normal microbiota).
Effectiveness of Antibiotic
Microbiologists conduct Kirby-Bauer tests to
determine the effectiveness of an antibiotic.
◦ a zone of inhibition is measured to determine the
effectiveness of an antibiotic.
An pathogen can be either:
◦ resistant
◦ intermediate
◦ susceptible
 Safety and Side Effects
1. Toxicity: many drugs have side effects.
◦ Polymyxcins and aminoglycosides have toxic
effects on kidneys, often fatal effects.
◦ Pregnant women and specifically fetuses are at
most risk.

Azole tetracyline
Safety and Side Effects
2. Allergies: many drugs trigger allergic responses.
◦ Penicllin allergies occur in 0.1% of the population.

3. Disruption of Normal Microbiota: death of normal

microbiota may result in a secondary infection
• Candida albicans (yeast) infection of vagina and
mouth often increase during application of broad
spectrum antibiotics.
• These are considered superinfections due to
uncontrolled growth.
Safety and Side Effects
4. Antibiotic resistant organisms
• In the absence of antibiotics, resistant cells are less
efficient in growth compared to normal cells.
• In the presence of antibiotics, normal cells die,
allowing for the resistant cells to take over a
population due to less competition.
Thought Questions
 QUESTION I: How can cells obtain antibiotic resistance?

 QUESTION II: Why do resistant strains of bacteria develop

more often in hospitals and nursing homes?
Examples of organisms that often require
multiple antibiotic resistance include:
◦ Staphylococcus
Vancomycin-resistant
Staphylococcus aureus
◦ Enterococcus

◦ Pseudomonas

◦ Mycobacterium

◦ Plasmodium