Antimicrobial Drugs

General Concepts
Antibiotics: antibacterial agents
Naturally occurring (Penicllin)
Semi-synthetic: slight alterations to naturally
occurring agents
Synthetics: synthesized
in the laboratory

General Concepts
It is important that any antibiotic demonstrate
selective toxicity.
The drug must be more toxic to a pathogen than a
pathogens 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
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?
Eukaryotic
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

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.
Azoles inhibit ergosterol
synthesis

1. CLOTRIMAZOLE
(LOTRIMIN),
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
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

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
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.
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
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.
tetracyline
Azole
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

Enterococcus

Pseudomonas

Mycobacterium

Plasmodium

Vancomycin-resistant
Staphylococcus aureus