Tutorial 9 notes Super Bug: Antibiotics & Evolution Kristy J. Wilson Department of Pathology Emory University History of Antibiotics http://videos.howstuffworks.com/science-channel/29783-100-greatest-discoveries-penicillinvideo.htm 1928: Alexander Fleming (re)discovers penicillin 1939: Howard Walter Florey, Ernst Chain and Norman Heatley purify penicillin à Folk medicine pre-dating Fleming s discovery often used moldy bread as treatment Sam just returned from a trip to India. She has a UTI and is at the hospital. She s not too worried she has had UTIs before and they are easily treated with a course of antibiotics. She is discussing the issue with her doctor, This looks like quite the serious infection. Sam replies, I wish I would have just gotten some cheap antibiotics in India. You don t even need a prescription there! Shortly after, Sam is moved into her own room. She s not too sure what s going on, but the doctor told her that she has the New Delhi Super Bug. Sam is in the room alone waiting for more test results. She s getting bored and starts Googling super bugs. Here is one of the visuals she finds: Clicker Question 1 How do you interpret this visual: A. Increased exposure to antibiotics results in decreased antibiotic resistance B. Decreased exposure to antibiotics results in increased antibiotic resistance

C. Increased exposure to antibiotics results in increased antibiotic resistance Clicker Question 2 What is the main cause of antibiotic resistant bacteria? A. Doctors overprescribing antibiotics B. Patients not taking the full course of antibiotics C. Governments not regulating antibiotic prescriptions D. Pharmaceutical companies not developing new antibiotics Sam also found this explanation on another website: Doctors in India aren t surprised that the Super Bug probably originated there. Drug control there is poor and common antibiotics have become ineffective in India. Some reasons may be because people can buy powerful antibiotics over the counter, leading to overuse. They also take small doses and discontinue treatment in order to save money. There are no current antibiotics, nor any in development, that can kill New Delhi Super Bug on their own. Vinny Ciancio (AccessRx) http://www.youtube.com/watch?v=5zuzmnbitdi&feature=relmfu Sam picked up the copy of Atlantic magazine left by the nurse and flipped to the article Resistance is Futile. She read: Firms are not developing antibiotics as fast as they used to. According to the Infectious Diseases Society of America (IDSA), between 1983 and 1987, the FDA approved 16 new antibacterial drugs for use in humans; from 2003 to 2007, it approved six. Megan McArdle (The Atlantic) Sam wondered exactly how bacteria become resistant to antibiotics. She searched the web and found this: Multi drug-resistant bacteria have been around for decades. In fact, the so called super bug is not actually a bug at all. Instead, the drug resistance comes from a gene called NDM-1 that gets passed from one kind of bacteria to another. These genes have sparked even more concerns because they don t lie in the genomes of the bacteria themselves. Instead, they sit on small, circular pieces of DNA called plasmids, which can be passed between bacteria. Emily Sohn (Discovery News) Clicker Question 3

How are plasmids transferred from one bacterium to another? A. Transduction: bacteria-specific viruses transfer DNA between two closely related bacteria. B. Transformation: parts of DNA normally present in the external environment are taken up by the bacteria. C. Conjugation: direct cell-cell contact between two bacteria (which need not be closely related). D. All of the above. Horizontal gene transfer: the NDM-1 gene has spread across several bacterial species NDM-1: New Delhi metallo-beta-lactamase 1 à enzyme that makes bacteria resistant to a broad range of antibiotics NDM-1 enzymes inactivate antibiotics by breaking them down http://www.youtube.com/watch?v=xoqzdem4z_s Clicker Question 4 True or False: In most cases, a significantly larger dosage of antibiotics is needed to treat NDM- 1 bacterial infections. A. True B. False x-axis: specific antibiotic tested (and class of antibiotic) y-axis: amount of antibiotics needed to kill the bacteria (log scale) à Each class of antibiotic works to disrupt the bacterial life cycle in a different way! NDM-1 inactivates nearly all of them. Clicker Question 5 In the case of Ampicillin, how much more antibiotic is needed to treat E. coli with NDM-1? A. The same amount B. 10 X as much

C. 100 X as much D. 1000 X as much How do bacteria evolve antibiotic resistance? Several E. coli isolates were collected from patients with UTIs similar to Sam s These isolates were examined for quinolone-specific resistance and the presence of mutations in the gyra and parc DNA sequences How do bacteria evolve antibiotic resistance? Quinolone is a class of antibiotics à the mechanism is to prevent DNA replication DNA replication requires the separation of DNA strands à two enzymes responsible: DNA gyrase (gyra) and topoisomerase IV (parc) Mutations in these two enzymes may prevent the action of quinolone antibiotics How do bacteria evolve antibiotic resistance? Several key mutations can confer resistance to the quinolone class of antibiotics A minimum of three mutations are required to confer quinolone resistance to E. coli bacteria Only three amino acid changes are required for antibiotic resistance! Clicker Question 6 Which of the following would be most likely to increase the resistance of bacteria to more than one class of antibiotics? A. Mutations in gyra B. Mutations in parc C. Mutations in both gyra and parc D. Expression of NDM-1

As Sam continued to read about superbugs, she realized that there are many aspects to the increased antibiotic resistance of bacteria. Pharmaceutical companies, government regulation, medical practices and personal use all contribute to this increasingly prevalent problem. More than 70% of the bacteria that cause hospital-acquired infections are resistant to at least one of the drugs most commonly used to treat them New antibiotics are not profitable to develop! It takes ~$500 million and 12-15 years to approve a new antibiotic Resistance generally develops in 1-5 years In 1950, agricultural scientists discovered that low doses of antibiotics make chickens grow faster à there is no regulation for the amount of antibiotic used Decreased antibiotic use may lead to increased food prices Antibiotic use allows for more animals to be raised on less space More than 50 million unnecessary prescriptions are written per year Over 50% of patients don t finish their prescriptions Many common household items now contain anti-microbial ingredients Parents and patients often demand antibiotics even if it is unlikely to help Clicker Question 7 What is the main cause of antibiotic resistant bacteria? A. Doctors overprescribing antibiotics B. Patients not taking the full course of antibiotics C. Governments not regulating antibiotic prescriptions

D. Pharmaceutical companies not developing new antibiotics