Evolving Antibiotics and other Fairy Tales The Quest for the “Perfect Antibiotic” by Chris Engdahl

1. Evolving Antibioticsand other Fairy TalesThe Quest for the “Perfect Antibiotic”by Chris Engdahl

2. Antibiotic Resistance • Mutations create novel antibiotic antagonists (β-lactamase) • Strong selective pressures (i.e. antibiotics) eliminate nonresistant strains • Interspecies competition promotes virulence factors • Those strains immune survive to reproduce

3. Antibiotic Resistance • Methicillin-resistant Staph. aureus (MRSA) • Vancomycin-resistant enterococcus (VRE) • Streptococcus pneumoniae • Salmonella • Campylobacter • Pseudomonas aeruginosa (Burn victims) • Escherichia coli • And many, many more…

4. Antibiotic Resistance • Graphic example of natural selection and evolution in action • Novel antibiotics quickly lose efficacy • New resistant strains emerge fast

5. Are We Screwed? (Perhaps not…)

6. Ganges River, 1896 • Considered a dirty river • Bacteriologist Ernest Hankin determines an unfilterable antimicrobial agent preventing cholera outbreaks

7. Paris, 1917 • Félix d'Hérelle discovers "an invisible, antagonistic microbe of the dysentery bacillus…” • “... a virus parasitic on bacteria.“ • Call his discovery a bacteriophage (“bacteria-eater”) • Forgotten to Western Medicine with the Antibiotic Revolution (but not to Russia)

8. Enter the PhageBacteria’s Natural Predator • 9×108 virions/mm in oceans • Arguably the most abundant life form on earth • Infects 70% of marine bacteria

9. Bacteriophage Life Cycle

10. Corynebacterium diphtheriae Listeria monocytogenes Escherichia coli Salmonella typhi Multidrug Resistant Staphylococcus Areus (MRSA) Streptococcus pneumoniae Pseudomonas aeruginosa Shigela dysenteriae Vibrio cholerae Klebsiella pneumoniae Clostridium perfringens Phage antagonists exist for the following pathogens

11. Benefits of Phage Therapy • Target specific • Quick, easy, and cheap to grow • “Evolving antibiotic” • No documented side effects (GRAS organisms)

12. Shortcomings • Body may mount immune response, decreasing efficacy • Not all bacteria have a phage antagonist …yet • Public perception • Traditional stereotypes (Russian) • Ineffective against viral infections

13. In Summary • Phage Therapy is a novel, effective and evolving treatment for many bacterial infections • Largely untested due to public perception (“live virus syndrome”) and Cold War politics • Potential for genetic manipulation and enhancement • Some Phase 1 clinical trials in progress now in Lubbock, TX • FDA approved for meat processing against Listeria monocytogenes

14. Bibliography Articles • Brüssow H "Phage therapy: the Escherichia coli experience“. Microbiology (2005) v. 151, p.2133-2140. • Soothill JS (1994). "Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa". Burns 20 (3): 209–11. • Duckworth DH, Gulig PA (2002). "Bacteriophages: potential treatment for bacterial infections". BioDrugs 16 (1): 57–62. • Pirisi A (2000). "Phage therapy—advantages over antibiotics?". Lancet 356 (9239): 1418. • "Stalin's Forgotten Cure" Science 25 October 2002 v.298 • Thiel, Karl (January 2004). "Old dogma, new tricks—21st Century phage therapy". Nature Biotechnology (London UK: Nature Publishing Group) 22 (1): 31–36. • Wommack KE, Colwell RR (March 2000). "Virioplankton: viruses in aquatic ecosystems". Microbiol. Mol. Biol. Rev. 64 (1): 69–114. Hyperlinks • http://www.cfsan.fda.gov/~rdb/opa-g198.html - FDA Agency Response Letter GRAS Notice No. GRN 000198 • http://www.youtube.com/watch?v=9hzUjx_oD8E - Bacteriophage life cycle a la Youtube • http://www.phage.ulaval.ca/index.php?pageDemandee=1 - Félix d'Hérelle Reference Center for Bacterial Viruses • www.phagetherapycenter.com/ - Phage Therapy Center of Tbilsi, Georgia. “…effective treatment solution for patients who have bacterial infections that do not respond to conventional antibiotics”