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Evolving AntibioticsEvolving Antibiotics and other Fairy Talesand other Fairy Tales

The Quest for the “Perfect Antibiotic”The Quest for the “Perfect Antibiotic”by Chris Engdahlby Chris Engdahl

Antibiotic ResistanceAntibiotic Resistance

• Mutations create novel antibiotic Mutations create novel antibiotic antagonists (antagonists (ββ-lactamase)-lactamase)

• Strong selective pressures (i.e. antibiotics) Strong selective pressures (i.e. antibiotics) eliminate nonresistant strainseliminate nonresistant strains

• Interspecies competition promotes Interspecies competition promotes virulence factorsvirulence factors

• Those strains immune survive to Those strains immune survive to reproducereproduce

Antibiotic ResistanceAntibiotic Resistance

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

Antibiotic ResistanceAntibiotic Resistance

• Graphic example of natural selection and evolution in action

• Novel antibiotics quickly lose efficacy

• New resistant strains emerge fast

Are We Screwed?Are We Screwed?

(Perhaps not…)(Perhaps not…)

Ganges River, 1896

• Considered a dirty river

• Bacteriologist Ernest Hankin determines an unfilterable antimicrobial agent preventing cholera outbreaks

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)

Enter the PhageEnter the PhageBacteria’s Natural PredatorBacteria’s Natural Predator

• 9×108 virions/mm in oceans

• Arguably the most abundant life form on earth

• Infects 70% of marine bacteria

Bacteriophage Life Cycle

Phage antagonists Phage antagonists exist for the following exist for the following

pathogenspathogens

• Corynebacterium diphtheriaeCorynebacterium diphtheriae • Listeria monocytogenesListeria monocytogenes• Escherichia coliEscherichia coli• Salmonella typhiSalmonella typhi• Multidrug ResistantMultidrug Resistant

Staphylococcus Areus (MRSA)Staphylococcus Areus (MRSA)• Streptococcus pneumoniaeStreptococcus pneumoniae • Pseudomonas aeruginosa Pseudomonas aeruginosa • Shigela dysenteriaeShigela dysenteriae • Vibrio choleraeVibrio cholerae• Klebsiella pneumoniaeKlebsiella pneumoniae• Clostridium perfringensClostridium perfringens

Benefits of Benefits of Phage TherapyPhage Therapy

• Target specificTarget specific

• Quick, easy, and Quick, easy, and cheap to growcheap to grow

• ““Evolving antibiotic”Evolving antibiotic”

• No documented side No documented side effects (GRAS effects (GRAS organisms)organisms)

ShortcomingsShortcomings

• Body may mount Body may mount immune response, immune response, decreasing efficacydecreasing efficacy

• Not all bacteria have Not all bacteria have a phage antagonist …a phage antagonist …yetyet

• Public perceptionPublic perception• Traditional Traditional

stereotypes (Russian)stereotypes (Russian)• Ineffective against Ineffective against

viral infectionsviral infections

In SummaryIn Summary• Phage Therapy is a novel, effective Phage Therapy is a novel, effective

and evolving treatment for many and evolving treatment for many bacterial infectionsbacterial infections

• Largely untested due to public Largely untested due to public perception (“live virus syndrome”) perception (“live virus syndrome”) and Cold War politicsand Cold War politics

• Potential for genetic manipulation Potential for genetic manipulation and enhancementand enhancement

• Some Phase 1 clinical trials in Some Phase 1 clinical trials in progress now in Lubbock, TXprogress now in Lubbock, TX

• FDA approved for meat processing FDA approved for meat processing against against Listeria monocytogenesListeria monocytogenes

BibliographyBibliographyArticlesArticles

• Brüssow H "Phage therapy: the Escherichia coli experience“. Brüssow H "Phage therapy: the Escherichia coli experience“. MicrobiologyMicrobiology (2005) v. 151, p.2133-2140. (2005) v. 151, p.2133-2140.• Soothill JS (1994). "Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa". Soothill JS (1994). "Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa". BurnsBurns 20 20

(3): 209–11. (3): 209–11. • Duckworth DH, Gulig PA (2002). "Bacteriophages: potential treatment for bacterial infections". Duckworth DH, Gulig PA (2002). "Bacteriophages: potential treatment for bacterial infections". BioDrugsBioDrugs 16 (1): 16 (1):

57–62.57–62.• Pirisi A (2000). "Phage therapy—advantages over antibiotics?". Pirisi A (2000). "Phage therapy—advantages over antibiotics?". LancetLancet 356 (9239): 1418. 356 (9239): 1418.• "Stalin's Forgotten Cure" "Stalin's Forgotten Cure" ScienceScience 25 October 2002 v.298 25 October 2002 v.298• Thiel, Karl (January 2004). "Old dogma, new tricks—21st Century phage therapy". Thiel, Karl (January 2004). "Old dogma, new tricks—21st Century phage therapy". Nature BiotechnologyNature Biotechnology (London (London

UK: Nature Publishing Group) 22 (1): 31–36.UK: Nature Publishing Group) 22 (1): 31–36.• Wommack KE, Colwell RR (March 2000). "Virioplankton: viruses in aquatic ecosystems". Wommack KE, Colwell RR (March 2000). "Virioplankton: viruses in aquatic ecosystems". Microbiol. Mol. Biol. Microbiol. Mol. Biol.

Rev. Rev. 64 (1): 69–114.64 (1): 69–114.

Hyperlinks Hyperlinks • http://www.cfsan.fda.gov/~rdb/opa-g198.html - FDA Agency Response Letter http://www.cfsan.fda.gov/~rdb/opa-g198.html - FDA Agency Response Letter GRAS Notice No. GRN 000198GRAS Notice No. GRN 000198• http://www.youtube.com/watch?v=9hzUjx_oD8E - Bacteriophage life cycle http://www.youtube.com/watch?v=9hzUjx_oD8E - Bacteriophage life cycle a laa la Youtube Youtube• http://www.phage.ulaval.ca/index.php?pageDemandee=1 - Félix d'Hérelle Reference Center for Bacterial Viruses 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 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” patients who have bacterial infections that do not respond to conventional antibiotics”