Transcript Work Day 1
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