Antimicrobial Drugs

Rangkuman
oleh
Ami Soewandi
 Paul Ehrlich
• He observed that certain dyes stain
bacterial cells and not animal cells
• Theorized that there could be a dye or
chemical that would harm bacterial cells
but not human cells
• Systematic search for chemical to cure
syphilis
• 606th compound tested proved to be highly
effective in treating laboratory animals
 Gerhard Domagk
• Discovered red dye, Prontosil effective in
treating Streococcal infections in animals
• No effect in test tubes
• Enzymes in animals blood split Prontosil
molecule into sulfanilamide- this acted
against streptococcal
• Sulfa Drug
 Alexander Fleming
• Working on cultures of Staphylococcus
• Contamination with mold
• Noticed colonies growing near mold
looked odd
• Found that mold was secreting substance
that was killing bacteria
Figure 20.1
 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
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?
 Antibacterial Drugs
Sulfa drugs were the first antibacterial drug.
Sulfanilamide acts by replacing para-
aminobenzoic acid that bacteria need to
manufacture folic acid.

© 2010 Pearson Prentice Hall, 18/9

Inc.
 Antibacterial Drugs
Penicillins are antibiotic substances. Antibiotics
are soluble substances derived from molds or
bacteria that inhibit the growth of other
microorganisms. Penicillins work by inhibiting
the enzymes that bacteria use to make their cell
walls.

© 2010 Pearson Prentice Hall, 18/10

Inc.
 Antibacterial Drugs
Cephalosporins
Bacteria have evolved
resistances to certain
antibiotics. Scientists
are working to develop
new and more potent
antibiotics to kill
resistant bacteria.
Penicillins have been
partially replaced by
cephalosporins, such
as cephalexin (Keflex).
© 2010 Pearson Prentice Hall, 18/11
Inc.
 Antibacterial Drugs
Tetracyclines are broad-
spectrum antibiotics that act
by binding to bacterial
ribosomes, inhibiting protein
synthesis.

© 2010 Pearson Prentice Hall, 18/12

Inc.
 Antibacterial Drugs
Fluoroquinolones are broad-spectrum
antibiotics first introduced in 1986. They act by
inhibiting DNA replication through the
interference with the enzyme DNA gyrase.
Ciprofloxacin (Cipro®) is the leading
fluoroquinolone.

© 2010 Pearson Prentice Hall, 18/13

Inc.
 Viruses and Antiviral Drugs
Viruses are
composed of nucleic
acids and proteins.
Viral diseases cannot
be cured by
antibiotics.

© 2010 Pearson Prentice Hall, 18/14

Inc.
 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(β)-lactams
• Prevent cross-linkage of NAM subunits
– Example: Penicillin
Beta(β)-lactams
 Cephalosporins (beta(β)-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 Prokaryotic

THOUGHT QUESTION: Why is

the bacterial ribosome a
good target for antimicrobial
drugs?
 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
1. CLOTRIMAZOLE
• Two anti-fungal drugs
(LOTRIMIN®),
exploit this fact:
2. MICONAZOLE
– Polyenes attach to (MICATIN®),
ergosterol in the
3. FLUCONAZOLE
membrane.
(DIFLUCAN®)
– Azoles inhibit ergosterol
synthesis
 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.

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