the genetics of antibiotic resistance research theme: infectious diseases jason kuehner march 5,...

The Genetics of Antibiotic Resistance

Research Theme:Infectious Diseases

Jason KuehnerMarch 5, 2007

http://scientificteaching.wisc.edu/video

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


• 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



Medical professional that deals with the incidence,distribution, and possible control of diseases

The Problem



Oral antibiotic approved for treatment of manycommon bacterial infections

The Problem



Species of bacteria that is the causative agent ofgonorrhea, a sexually transmitted infection

The Problem



• 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



• 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

• Sexually transmitted infection caused by the bacterium Neisseria gonorrhoeae

• Among the most common sexually transmitted infections (STI) in the world

What is gonorrhea?

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

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

Mold colony(Penicillium chrysogenum)

Bacteria

Gonorrhea is treated with antibiotics

• Antibiotics help cure infections by decreasing the bacterial population to a level that the human immune system can handle

Antibiotictreatment

Antibiotics disrupt essential cell processes


Outer cellmembrane

Cell wall

Inner cellmembrane

+ antibiotic(e.g. Penicillin)

Cell wallconstruction


Cell wallconstruction


RNA

DNA

Protein

Gene expression


RNA

DNA

• Enzymes• Cell structure• Signaling

Protein

Gene expression

DNA replication occurs prior to cell division

DNA replication

Parent Cell

Daughter Cells

DNA


Replication

DNA

Gene expression


Transcription

Replication

DNA

Gene expression

RNA


Transcription

Translation

Replication

DNA

Gene expression

RNA

Protein


Transcription

Translation

Replication

“Central Dogmaof molecularbiology”

RNA

Protein

DNA

Gene expression


Transcription

Translation

Replication+ antibiotic

RNA

Protein

DNA


Transcription

Translation

Replication+ antibiotic Gene

expression

RNA

Protein

DNA

What is antibiotic resistance?

• The ability of bacteria to survive exposure to antibiotic drugs

Antibiotictreatment

Resistance through alteration of drug target

Enzyme active site

antibiotic

Wild typeprotein

Mutantprotein

Resistance through alteration of drug target

antibiotic

Wild typeprotein

Mutantprotein

antibiotic

Enzyme active site Enzyme active site

DNA mutation can alter protein structure

Wild type Mutant

RNA

Protein

DNA

Genotype codes for the phenotype

Every living organism is the outward physical manifestation of internally coded, inheritable, information


Every living organism is the outward physical manifestation of internally coded, inheritable information

Genotype: The geneticconstitution of an organism


Every living organism is the outward physical manifestation of internally coded, inheritable, information

Genotype: The geneticconstitution of an organism

Phenotype: The physicalfeatures of an organismproduced by the interactionof genotype and environment


RNA

Protein

DNA Genotype

Phenotype

AntibioticSensitivity

antibiotic

(Wild type)


RNA

Protein

DNA Genotype

Phenotype

AntibioticResistance

antibiotic

(Mutant)

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.

Genotype can perturb phenotype

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

Gonococcal Isolate Surveillance Project (GISP) — Percent of Neisseriagonorrhoeae isolates with resistance or intermediate resistance to ciprofloxacin, 1990–2005

CDC STD Surveillance, 2005

Increasing resistance to antibiotics in US

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

+ + +Variation Heredity TimeSelectivePressure

http://evolution.berkeley.edu


Variation



VariationSelectivePressure



Variation HereditySelectivePressure



Variation Heredity TimeSelectivePressure

Why aren’t antibiotics as effective as they used to be?


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.






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.


the genetics of antibiotic resistance research theme: infectious diseases jason kuehner march 5,...

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