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Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance
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Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance

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March’s SHOW focused on the growing trend in microbial drug resistance. Pathogenic bacteria resistant to many or all antibiotics already exist. Coupled with the rapid decline in microbiological …

March’s SHOW focused on the growing trend in microbial drug resistance. Pathogenic bacteria resistant to many or all antibiotics already exist. Coupled with the rapid decline in microbiological research at pharmaceutical companies, the rapid rate at which resistance has evolved and spread has demanded a novel approach to addressing this critical human health issue.

Published in: Health & Medicine, Technology
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  • 1. The Antibiotic Perfect Storm Shifting the paradigm of antibiotic discovery and development5/26/2012 Bacteriotix - Science Shaping our World 1
  • 2. 5/26/2012 Bacteriotix - Science Shaping our World 2
  • 3. The antibiotic and resistance pipelines converge Clatworthy, et al. 2007. Nature Chemical Biology 3, 541 – 548.5/26/2012 Bacteriotix - Science Shaping our World 3
  • 4. Why no new drugs?• Resistance rapidly emerges and spreads, limiting antibiotic shelf-life and returns on investment• Limited duration of antibiotic use results in lower returns on investment• The price paid by consumers does not reflect the relative effectiveness of the drug, i.e. it saves lives!• Targeting new antibiotic mechanisms represents significant risk to investors 5/26/2012 Bacteriotix - Science Shaping our World 4
  • 5. Medically relevant bacteria Gram-positives Gram-negatives Staphylococcus Pseudomonas Streptococcus Neisseria Corynebacter Legionella Listeria Haemophilus Bacillus Klebsiella Clostridia… Escherichia Salmonella Helicobacter Proteus Enterobacter Serratia… Very few lineages to target5/26/2012 Bacteriotix - Science Shaping our World 5
  • 6. Humans as microbial fermenter 9 of every 10 cells in the human body are microbial few are ever pathogenic5/26/2012 Bacteriotix - Science Shaping our World 6
  • 7. Microbes-R-Us Most contribute positively to human health or are even required for life5/26/2012 Bacteriotix - Science Shaping our World 7
  • 8. Current approach to treating infectious disease Toxicity Resistance Allergic reactions Immune suppression Destruction of beneficial gut flora Overgrowth of pathogens And - they are less effective over time H bomb explosion on Marshall Islands, 1952 Broad spectrum antibiotics decimate normal, healthy microbial community5/26/2012 Bacteriotix - Science Shaping our World 8
  • 9. Few lineages make or use antibiotics Eucaryotic molds (Pencillium and Cephalosporium) Two types of spore-forming bacteria (Actinomycetes and Bacillus)5/26/2012 Bacteriotix - Science Shaping our World 9
  • 10. Most pathogens live in biofilms Naturally resistant to antibiotics5/26/2012 Bacteriotix - Science Shaping our World 10
  • 11. Use of Broad Spectrum Antibiotics– Ecologically unsound • uncommon in natural populations– Selects for massive resistance • target populations are immense– Maintains resistance • selection for resistance is maintained • resistance costs are ameliorated– Ineffective against many pathogens • High levels of resistance • Can’t penetrate biofilms– Devastates the healthy flora • opens door to opportunistic pathogens5/26/2012 Bacteriotix - Science Shaping our World 11
  • 12. Think outside the box How would bacteria solve this problem? Bacteriotix Employing ecologically sound approaches to meet the challenges of antibiotic resistance5/26/2012 Bacteriotix - Science Shaping our World 12
  • 13. The guided missile approach Most bacteria employ narrow spectrum toxins to fend off invaders or competitors - kill their closest relatives -5/26/2012 Bacteriotix - Science Shaping our World 13
  • 14. Bacteriocins the microbial weapon of choice • All Archeae • All Bacteria • Many/most microbial Eucarya • Common bacteriocins – Colicins – Nisin – Pediocin – Pyocins – Lacticin Easy to find5/26/2012 Bacteriotix - Science Shaping our World 14
  • 15. Bacteriocin structure and function Kleanthous (2010) Mol. Microbiol 75, 5295/26/2012 Bacteriotix - Science Shaping our World 15
  • 16. The true “designer” drugZouhir, et al. 2010. A new structure-based classification of Gram-positive bacteriocins. Protein J., 29: 432-439.5/26/2012 Bacteriotix - Science Shaping our World 16
  • 17. How narrow is narrow-spectrum? Riley et al. 2005. JME 54: 210-2185/26/2012 Bacteriotix - Science Shaping our World 17
  • 18. BacteriocinsLong history of use in food preservation FDA - GRAS5/26/2012 Bacteriotix - Science Shaping our World 18
  • 19. New interest in bacteriocin use in human health• MIC’s comparable to antibiotics5/26/2012 Bacteriotix - Science Shaping our World 19
  • 20. As effective as antibiotics 100 90 80 70 Inhibitory Percentage 60 50 40 30 20 10 0 am sam δ cip E4 sxt β α E9 H cz γ fox ft gm Bacteriocin/ Antibiotic 400 uropathogenic strains of E. coli – comparable or lower MIC’s Riley et al, unpublished5/26/2012 Bacteriotix - Science Shaping our World 20
  • 21. New interest in bacteriocin use in human health• MIC’s comparable to antibiotics• Act in synergy with antibiotics5/26/2012 Bacteriotix - Science Shaping our World 21
  • 22. Effective in combination therapiesKiri et al. 2002. Combinations of lysostaphin with beta-lactams are synergistic against oxacillan-resistance Staphylococcus epidermis. AAC 46: 2017-2020.5/26/2012 Bacteriotix - Science Shaping our World 22
  • 23. New interest in bacteriocin use in human health• MIC’s comparable to antibiotics• Act in synergy with antibiotics• Breaks down biofilms5/26/2012 Bacteriotix - Science Shaping our World 23
  • 24. Effective in biofilms Smith et al., 2012. Activity of Pyocin S2 against Pseudomonas aeruginosa Biofilms. AAC 56(3):1599.5/26/2012 Bacteriotix - Science Shaping our World 24
  • 25. Effective in biofilmsNel et al. 2002.Effect of bacteriocin pediocin PD-1, plantaricin 423, and nisin on biofilmsof Oenococcus oeni on a stainless steel surface. Am. J. Enol. Vitic. 53: 191-197. 5/26/2012 Bacteriotix - Science Shaping our World 25
  • 26. New interest in bacteriocin use in human health• MIC’s comparable to antibiotics• Act in synergy with antibiotics• Breaks down biofilms• Effective in vivo5/26/2012 Bacteriotix - Science Shaping our World 26
  • 27. In vivo activity in renal infections Dixon et al. 1968. Lystostaphin: an enzymatic approach to staphylococcal disease. JBM. 41: 62-69.5/26/2012 Bacteriotix - Science Shaping our World 27
  • 28. In vivo activity in aortic valve infections Patron et al. 1999. Lysostaphin treatment of experimental aortic valve endocarditiscaused by a Staphylococcus aureus isolated with reduced susceptibility to vancomycin. AAC 43: 1754-1755.5/26/2012 Bacteriotix - Science Shaping our World 28
  • 29. In vivo activity in liver infectionsIngham et al., 2003. The bacteriocin piscicolin 126 retains antilisterial activity in vivo. JAC 51: 1365-1371.5/26/2012 Bacteriotix - Science Shaping our World 29
  • 30. New interest in bacteriocin use in human health • MIC’s comparable to antibiotics • Act in synergy with antibiotics • Breaks down biofilms • Effective in vivo • Reduced selection pressures for resistance5/26/2012 Bacteriotix - Science Shaping our World 30
  • 31. Resistance mutation rates Mutation ratethe number of mutation events per gene per unit of time Broad spectrum antibiotics is ~1 x 10-6 Bacteriocins: roughly the same rate Mutational targets Broad spectrum antibiotics is >>1012 Bacteriocins is minimal, <<1065/26/2012 Bacteriotix - Science Shaping our World 31
  • 32. Resistance is costlyDykes et al. 2002. Fitness costs associated with class IIa bacteriocin resistance in Listeria moncytogenes. LAM 26: 5-8.5/26/2012 Bacteriotix - Science Shaping our World 32
  • 33. Resistance can be delayed Riley et al., Unpublished5/26/2012 Bacteriotix - Science Shaping our World 33
  • 34. Colicin cocktail creation Riley et al., Unpublished5/26/2012 Bacteriotix - Science Shaping our World 34
  • 35. Bacteriocin advantages• Easy to find• Highly specific• Low MIC’s• Long history of use in food preservation – GRAS status• Active in vivo (in animal blood, liver and kidney, human serum, oral cavity, intestine, urinary tract infections)• Active against non-dividing and dividing cells and biofilms• Little to no toxicity to human cells, no immune reaction• Ease of genetic manipulation and production• Reduced resistance levels and high cost of resistance 5/26/2012 Bacteriotix - Science Shaping our World 35
  • 36. Bacteriotix, LLC Product pipeline• Urinary tract infections• In-dwelling urethral catheters• Superficial skin infections• Lung infections of patients with cystic fibrosis5/26/2012 Bacteriotix - Science Shaping our World 36
  • 37. Effective in catheters Trautner et al. 2005. Colicins prevent colonization of catheters. JAC 56:413-415.5/26/2012 Bacteriotix - Science Shaping our World 37
  • 38. Colicins effective in UTI’s in vivo Riley et al., Unpublished5/26/2012 Bacteriotix - Science Shaping our World 38
  • 39. Superficial skin and burn infections DOD interested in developing bacteriocin-based gel for battlefield use against SSI’s Also interested in using them to limit density of pathogens in warfighters local environment – attaching bacteriocins to the surfaces of cots, tents, uniforms, etc.5/26/2012 Bacteriotix - Science Shaping our World 39
  • 40. Comments on creating a company• The good Turning basic science into applied, Potentially saving lives, Return on taxpayer’s investment, Perhaps creating a nice retirement fund…• The bad Entirely new approach – not in Kansas anymore, Raising capital – worse than grant-writing – if that is possible, Dealing with investors – I wouldn’t know yet – am open for that experience…• The ugly….. I already have a day-job! 5/26/2012 Bacteriotix - Science Shaping our World 40
  • 41. Rob Dorit Smith College Sandy Robinson Chris Roy Danielle Fedora Suphan Bakal Institute For Drug Resistance Jenna Farrell Shanika Collins Bacteriotix Partners & Collaborators5/26/2012 Bacteriotix - Science Shaping our World 41
  • 42. Institute for Drug Resistance New Gordon Conference on Drug Resistance AAM colloquium on drug resistance Over 4,000 members in 2 years5/26/2012 Bacteriotix - Science Shaping our World 42
  • 43. 5/26/2012 Bacteriotix - Science Shaping our World 43

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