Research Theme:
Infectious Diseases
The Genetics of Antibiotic Resistance
Jason Kuehner
March 5, 2007
http://scientificteaching.wisc.edu/video
What’s wrong with this statement?
• Take a few minutes to individually complete this
worksheet and then compare your answers with
your group
What’s wrong with this statement?
• Take a few minutes to individually complete this
worksheet and then compare your answers with
your group
• Consider these misconceptions throughout class
today and we’ll follow-up on them at the end
The Problem
The Problem
• You run a public health clinic in Racine, Wisconsin
The Problem
• You run a public health clinic in Racine, Wisconsin
• A county commissioner overseeing your clinic is
an epidemiologist and wants to know how you
plan to address the emergence of ciprofloxacin
resistance in Neisseria gonorrhoeae
The Problem
• You run a public health clinic in Racine, Wisconsin
• A county commissioner overseeing your clinic is
an epidemiologist and wants to know how you
plan to address the emergence of ciprofloxacin
resistance in Neisseria gonorrhoeae
Medical professional that deals with the incidence,
distribution, and possible control of diseases
The Problem
• You run a public health clinic in Racine, Wisconsin
• A county commissioner overseeing your clinic is
an epidemiologist and wants to know how you
plan to address the emergence of ciprofloxacin
resistance in Neisseria gonorrhoeae
Oral antibiotic approved for treatment of many
common bacterial infections
The Problem
• You run a public health clinic in Racine, Wisconsin
• A county commissioner overseeing your clinic is
an epidemiologist and wants to know how you
plan to address the emergence of ciprofloxacin
resistance in Neisseria gonorrhoeae
Species of bacteria that is the causative agent of
gonorrhea, a sexually transmitted infection
The Problem
• You run a public health clinic in Racine, Wisconsin
• A county commissioner overseeing your clinic is
an epidemiologist and wants to know how you
plan to address the emergence of ciprofloxacin
resistance in Neisseria gonorrhoeae
• State budget cuts mean you cannot afford to give
all of your patients more expensive antibiotics or
do all of the lab tests that you would like
The Problem
• You run a public health clinic in Racine, Wisconsin
• A county commissioner overseeing your clinic is
an epidemiologist and wants to know how you
plan to address the emergence of ciprofloxacin
resistance in Neisseria gonorrhoeae
• State budget cuts mean you cannot afford to give
all of your patients more expensive antibiotics or
do all of the lab tests that you would like
 Develop a plan to address the medical,
economic, and political questions your clinic will
face in dealing with this public health issue
What is gonorrhea?
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
• Sexually transmitted infection caused by the bacterium
Neisseria gonorrhoeae
• Among the most common sexually transmitted
infections (STI) in the world
Gonorrhea is treated with antibiotics
• Antibiotic: chemical substance produced by
or derived from a microorganism (molds or
bacteria) that kills or inhibits the growth of
bacteria
Bacteria
Mold colony
(Penicillium chrysogenum)
Gonorrhea is treated with antibiotics
• Antibiotics help cure infections by decreasing
the bacterial population to a level that the
human immune system can handle
Antibiotic
treatment
Antibiotics disrupt essential cell processes
Antibiotics disrupt essential cell processes
Antibiotics disrupt essential cell processes
Antibiotics disrupt essential cell processes
Cell wall
construction
Outer cell
membrane
Cell
wall
Inner cell
membrane
+ antibiotic
(e.g. Penicillin)
Antibiotics disrupt essential cell processes
Cell wall
construction
Antibiotics disrupt essential cell processes
Gene
expression
DNA
RNA
Protein
Antibiotics disrupt essential cell processes
Gene
expression
DNA
RNA
Protein
• Enzymes
• Cell structure
• Signaling
DNA replication occurs prior to cell division
DNA
Parent Cell
Daughter Cells
DNA replication
Antibiotics disrupt essential cell processes
Gene
expression
Replication
DNA
Antibiotics disrupt essential cell processes
Gene
expression
Replication
DNA
Transcription
RNA
Antibiotics disrupt essential cell processes
Gene
expression
Replication
DNA
Transcription
RNA
Translation
Protein
Antibiotics disrupt essential cell processes
“Central Dogma
of molecular
biology”
Gene
expression
Replication
DNA
Transcription
RNA
Translation
Protein
Antibiotics disrupt essential cell processes
+ antibiotic
Replication
DNA
Transcription
RNA
Translation
Protein
Antibiotics disrupt essential cell processes
+ antibiotic
Replication
DNA
Transcription
RNA
Translation
Protein
Antibiotics disrupt essential cell processes
+ antibiotic
Replication
DNA
Transcription
RNA
Translation
Protein
Antibiotics disrupt essential cell processes
Gene
expression
+ antibiotic
Replication
DNA
Transcription
RNA
Translation
Protein
What is antibiotic resistance?
• The ability of bacteria to survive exposure to
antibiotic drugs
Antibiotic
treatment
Resistance through alteration of drug target
antibiotic
Wild type
protein
Enzyme active site
Mutant
protein
Resistance through alteration of drug target
Wild type
protein
Mutant
protein
antibiotic
antibiotic
Enzyme active site
Enzyme active site
DNA mutation can alter protein structure
Wild type
Mutant
DNA
RNA
Protein
Genotype codes for the phenotype
Every living organism is the outward physical
manifestation of internally coded, inheritable,
information
Genotype codes for the phenotype
Every living organism is the outward physical
manifestation of internally coded, inheritable
information
Genotype: The genetic
constitution of an organism
Genotype codes for the phenotype
Every living organism is the outward physical
manifestation of internally coded, inheritable,
information
Genotype: The genetic
constitution of an organism
Phenotype: The physical
features of an organism
produced by the interaction
of genotype and environment
Genotype codes for the phenotype
DNA
Genotype (Wild type)
RNA
antibiotic
Protein
Phenotype
Antibiotic
Sensitivity
Genotype codes for the phenotype
Genotype (Mutant)
DNA
RNA
antibiotic
Protein
Phenotype
Antibiotic
Resistance
Genotype can perturb phenotype
The following statements describe how a change in genotype
can perturb phenotype. Number them in the best sequential
order (1=earliest event, 4=latest event):
__ Mutant RNA is translated.
__ Mutant DNA is transcribed.
__ Mutant protein is altered, changing an organism’s response
to its environment.
__ An error occurs during DNA replication, resulting in a gene
mutation.
Genotype can perturb phenotype
The following statements describe how a change in genotype
can perturb phenotype. Number them in the best sequential
order (1=earliest event, 4=latest event):
_3_ Mutant RNA is translated.
_2_ Mutant DNA is transcribed.
_4_ Mutant protein is altered, changing an organism’s response
to its environment.
_1_ An error occurs during DNA replication, resulting in a gene
mutation.
Emergence of antibiotic resistance
“It is not difficult to make microbes resistant to penicillin in the
laboratory by exposing them to concentrations not sufficient
to kill them, and the same thing has occasionally happened in
the body.”
- Alexander Fleming, 1945 Nobel Prize lecture
Increasing resistance to antibiotics in US
Gonococcal Isolate Surveillance Project (GISP) — Percent of Neisseria
gonorrhoeae isolates with resistance or intermediate resistance to
ciprofloxacin, 1990–2005
CDC STD Surveillance, 2005
Increasing resistance to antibiotics @ UW
• UHS Gonorrhea Isolation - 2006
– 26 total cases
•
•
•
•
Cervical/Vaginal (3)
Urethral/Urine (14)
Pharynx (4)
Rectal (5)
– 9/9 non-genital isolates tested were
ciprofloxacin resistant
Evolution of antibiotic resistance
Selective
Variation + Pressure
+
Heredity
+
Time
Evolution of antibiotic resistance
Variation
http://evolution.berkeley.edu
Evolution of antibiotic resistance
Variation
Selective
Pressure
http://evolution.berkeley.edu
Evolution of antibiotic resistance
Variation
Selective
Pressure
Heredity
http://evolution.berkeley.edu
Evolution of antibiotic resistance
Variation
Selective
Pressure
Heredity
Time
http://evolution.berkeley.edu
What’s wrong with this statement?
Why aren’t antibiotics as effective as they used to be?
What’s wrong with this statement?
1. People have become immune to antibiotics
– Human immune systems do not build up immunity to antibiotics.
Rather, it is the bacteria within the human host that become
resistant.
What’s wrong with this statement?
1. People have become immune to antibiotics
– Human immune systems do not build up immunity to antibiotics.
Rather, it is the bacteria within the human host that become
resistant.
2. Antibiotics are changing and subsequently becoming weaker
– Antibiotics are inert chemical substances. Bacteria, however, are
living organisms that can change through evolution.
What’s wrong with this statement?
1. People have become immune to antibiotics
– Human immune systems do not build up immunity to antibiotics.
Rather, it is the bacteria within the human host that become
resistant.
2. Antibiotics are changing and subsequently becoming weaker
– Antibiotics are inert chemical substances. Bacteria, however, are
living organisms that can change through evolution.
3. Bacteria have mutated in order to become resistant
– Bacteria do not “choose” to mutate, adapt, or develop resistance.
Natural selection selects among whatever variation exists in the
population and the result is evolution.
What’s wrong with this statement?
1. People have become immune to antibiotics
– Human immune systems do not build up immunity to antibiotics.
Rather, it is the bacteria within the human host that become
resistant.
2. Antibiotics are changing and subsequently becoming weaker
– Antibiotics are inert chemical substances. Bacteria, however, are
living organisms that can change through evolution.
3. Bacteria have mutated in order to become resistant
– Bacteria do not “choose” to mutate, adapt, or develop resistance.
Natural selection selects among whatever variation exists in the
population and the result is evolution.
4. Antibiotics have mutated bacteria to become resistant
– Antibiotics do not introduce mutations. Mutations occur randomly
during DNA replication.
Delaying the inevitable…
1. Don’t use antibiotics to treat viral infections.
2. Avoid mild doses of antibiotics over long time periods.
3. When treating a bacterial infection with antibiotics, take all
of your pills.
4. Use a combination of drugs to treat a bacterial infection.
5. Reduce or eliminate the “preventative” use of antibiotics on
livestock and crops.
http://evolution.berkeley.edu