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The Genetics of Antibiotic Resistance

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.

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The Genetics of Antibiotic Resistance

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  1. Research Theme: Infectious Diseases The Genetics of Antibiotic Resistance Jason Kuehner March 5, 2007

  2. http://scientificteaching.wisc.edu/video

  3. What’s wrong with this statement? • Take a few minutes to individually complete this worksheet and then compare your answers with your group

  4. 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

  5. The Problem

  6. The Problem • You run a public health clinic in Racine, Wisconsin

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. What is gonorrhea? • Sexually transmitted infection caused by the bacterium Neisseria gonorrhoeae • Among the most common sexually transmitted infections (STI) in the world

  14. 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)

  15. 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

  16. Antibiotics disrupt essential cell processes

  17. Antibiotics disrupt essential cell processes

  18. Antibiotics disrupt essential cell processes

  19. Antibiotics disrupt essential cell processes Cell wall construction Outer cell membrane Cell wall + antibiotic (e.g. Penicillin) Inner cell membrane

  20. Antibiotics disrupt essential cell processes Cell wall construction

  21. Antibiotics disrupt essential cell processes Gene expression DNA RNA Protein

  22. Antibiotics disrupt essential cell processes Gene expression DNA RNA • Enzymes • Cell structure • Signaling Protein

  23. DNA replication occurs prior to cell division Parent Cell DNA Daughter Cells DNA replication

  24. Antibiotics disrupt essential cell processes Gene expression Replication DNA

  25. Antibiotics disrupt essential cell processes Gene expression Replication DNA Transcription RNA

  26. Antibiotics disrupt essential cell processes Gene expression Replication DNA Transcription RNA Translation Protein

  27. Antibiotics disrupt essential cell processes “Central Dogma of molecular biology” Gene expression Replication DNA Transcription RNA Translation Protein

  28. Antibiotics disrupt essential cell processes + antibiotic Replication DNA Transcription RNA Translation Protein

  29. Antibiotics disrupt essential cell processes + antibiotic Replication DNA Transcription RNA Translation Protein

  30. Antibiotics disrupt essential cell processes + antibiotic Replication DNA Transcription RNA Translation Protein

  31. Antibiotics disrupt essential cell processes Gene expression + antibiotic Replication DNA Transcription RNA Translation Protein

  32. What is antibiotic resistance? • The ability of bacteria to survive exposure to antibiotic drugs Antibiotic treatment

  33. Resistance through alteration of drug target antibiotic Wild type protein Mutant protein Enzyme active site

  34. Resistance through alteration of drug target Wild type protein Mutant protein antibiotic antibiotic Enzyme active site Enzyme active site

  35. DNA mutation can alter protein structure Wild type Mutant DNA RNA Protein

  36. Genotype codes for the phenotype Every living organism is the outward physical manifestation of internally coded, inheritable, information

  37. 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

  38. Genotype codes for the phenotype Every living organism is the outward physical manifestation of internally coded, inheritable, information Phenotype: The physical features of an organism produced by the interaction of genotype and environment Genotype: The genetic constitution of an organism

  39. Genotype codes for the phenotype DNA Genotype (Wild type) RNA antibiotic Phenotype Protein Antibiotic Sensitivity

  40. Genotype codes for the phenotype Genotype (Mutant) DNA RNA antibiotic Phenotype Protein Antibiotic Resistance

  41. 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.

  42. 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.

  43. 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

  44. 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

  45. 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

  46. Evolution of antibiotic resistance Selective Pressure Heredity Time Variation + + +

  47. Evolution of antibiotic resistance Variation http://evolution.berkeley.edu

  48. Evolution of antibiotic resistance Selective Pressure Variation http://evolution.berkeley.edu

  49. Evolution of antibiotic resistance Selective Pressure Heredity Variation http://evolution.berkeley.edu

  50. Evolution of antibiotic resistance Selective Pressure Heredity Time Variation http://evolution.berkeley.edu

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