The superbugs are coming! T he race for new antibiotics

1. The superbugs are coming! The race for new antibiotics Dr Steven Cobb Chemistry Department Durham University s.l.cobb@durham.ac.uk Bacterial resistance and the generation of superbugs Is the situation really that bad? Antibiotics of the future: Research at Durham Summary Antibiotics beyond 2011 Bacteria: Friend or Foe? Fighting infectious bacteria Introducing antibiotics and the bacteria cell Penicillin: The wonder drug Vancomycin: The antibiotic of last resort Dr S. Cobb/ Durham University

2. Bacteria: Friend or Foe? Infectious bacteria (bad bacteria) Probiotic bacteria (good bacteria) Dr S. Cobb/ Durham University

3. Fighting infectious bacteria Cure Prevention Rest Time Antibiotics (drug molecules) Dr S. Cobb/ Durham University

4. What are antibiotics? Antibiotics are compounds that can be used to kill bacterial cells. Sulfonamidedrugs (late 1930s) Vancomycin(late 1950s) Penicillin(-lactams, 1940s) Dr S. Cobb/ Durham University

5. Antibiotic targets The cell is the most basic building block for life in all organisms. Structural differences between cell types (e.g. human and bacteria) can be used to design selective drugs. This has been carried out to great effect in the development of antibiotics. Dr S. Cobb/ Durham University

6. Human and bacterial cells Normal human cell Plasma Membrane (no cell wall) Dr S. Cobb/ Durham University

7. Antibiotics and the magic bullet effect Normal cells Bacteria Antibiotic Bacteria are killed and the normal cells left untouched Dr S. Cobb/ Durham University

8. Penicillin: The wonder drug of the 20th century The Nobel Prize in Physiology or Medicine 1945 Sir Alexander Fleming, Ernst Chain, Sir Howard Florey Ernst Chain Howard Florey Dr S. Cobb/ Durham University

9. Penicillin’s mode action against bacteria Dr S. Cobb/ Durham University

10. Penicillin’s mode action against bacteria Dr S. Cobb/ Durham University

11. Penicillin: The wonder drug of the 20th century Advantages Relatively inexpensive (compared to alternatives). In general non-toxic to patient. Disadvantages Not active against a broad spectrum of bacteria and not effective against Gram-negative bacteria. Unstable to acidic conditions thus can not be given in oral form. Simple mutations in bacteria can give rise to penicillin resistant strains. Can cause allergic reactions in some people (1-4% cases) which can be very serious. Fatality rates however are low 0.001%. Dr S. Cobb/ Durham University

12. Vancomycin: The antibiotic of last resort Scientists realized that Vancomycin was active against bacterial strains that had developed resistance to Penicillin-based drugs. Fast tracked by the FDA and since 1958, it has been a key player in the war against bacterial pathogens. It is commonly used when other drugs fail and thus it is widely known as the “antibiotic of last resort”. Vancomycin is a glyco-peptide (sugar-peptide) that was first isolated from Borneo jungle soil samples. Dr S. Cobb/ Durham University

13. Vancomycin: Mode of action Dr S. Cobb/ Durham University

14. Antibacterial resistance and the generation of superbugs Dr S. Cobb/ Durham University

15. Penicillin and antibacterial resistance Emergence of bacterial resistance to Penicillin detected as earlier as 1948 Dr S. Cobb/ Durham University

16. What causes bacterial resistance? Dr S. Cobb/ Durham University

17. The emergence of superbugs (MRSA) 1961: Emergence of bacterial resistance to Methicillin (Methicillin Resistant Staphylococusaureus, MRSA) Dr S. Cobb/ Durham University

18. What is different about MRSA? The enzyme that Methicillin targets is modified so that it can no longer fit in the active site ( = no inhibition of enzyme). Dr S. Cobb/ Durham University

19. Mutated peptide sequence in Vancomycinresistant bacteria Normal peptide sequence in vancomycin sensitive bacteria The emergence of superbugs (VRSA) Dr S. Cobb/ Durham University

20. Superbugs, is the situation really that bad? No effective drugs left Some drugs still effective and more on the way Dr S. Cobb/ Durham University

21. Superbugs, is the situation really that bad? Not so many Lots of drugs Dr S. Cobb/ Durham University

22. Superbugs, is the situation really that bad? Only three of the approved antibiotics in the last 10 years (25% of total) have of new mode of action Dr S. Cobb/ Durham University

23. The next generation of antibiotics Ideally any new antibiotic must have: New mode of action so it can be used against MRSA etc Non-toxic to human cells (magic bullet effect) http://en.wikipedia.org/wiki/List_of_antibiotics In my group we want to develop a new class of antibiotics that are derived from our bodies own defence system to infection, the innate immune response. Dr S. Cobb/ Durham University

24. Innate immunity What happens when you cut your finger? How does your body fight potential infection? Dr S. Cobb/ Durham University

25. Innate immunity What happens when you cut your finger? How does your body fight potential infection? Innate immunity – fast, brute force, no real plan, not coordinated Adaptive immunity- antibodies, highly effective, calculated Dr S. Cobb/ Durham University

26. The innate immune response in action The S. aureusbacteria grows but your skin releases a compound as part of the innate immune response that can kill the E. coli bacteria. Dr S. Cobb/ Durham University

27. The innate immune response in action Your skin releases a compound as part of innate immune response that can kill E. Coli bacteria. The compound is a peptide that is part of a range of antimicrobial peptides that the body can produce as a first line defence against infection. Dr S. Cobb/ Durham University

28. Antimicrobialpeptides Positively charged peptide molecules (charge typically between +2 to +9). They range in size from 12 to 100 amino acids in length. Extremely potent (nM) against a broad spectrum of bacteria including drug resistant strains (MRSA and VRSA) due to a different mode of action. Dr S. Cobb/ Durham University

29. Antimicrobial peptides Dr S. Cobb/ Durham University

30. Antimicrobial peptides and their selectivity for bacteria Dr S. Cobb/ Durham University

31. Antimicrobial peptides and their mode of action http://www.youtube.com/watch?v=9-HegAO4T0A Dr S. Cobb/ Durham University

32. Our research on antimicrobial peptides Antibacterial Surfaces New Drugs Dr S. Cobb/ Durham University

33. Summary Many of the antibiotics developed in the 1930s and 1940s are no longer active against the bacteria that they were designed to target. New strains of superbugs have been emerging since the 1960s. At present MRSA is the main problem, but VRSA represents a much bigger problem on the horizon. At the present time we are winning the fight against bacteria, but in the next 10 years……. Dr S. Cobb/ Durham University

34. Antibiotics beyond 2011…… The NHS The drug companies The academics The future……… Dr S. Cobb/ Durham University

35. I wonder how she’ll react when I tell her I need to got to the toilet again! This will keep you safe from that pesky VRSA. Going to school 2020? Dr S. Cobb/ Durham University

36. The superbugs are coming! The race for new antibiotics Any questions? Dr Steven Cobb Chemistry Department Durham University s.l.cobb@durham.ac.uk Dr S. Cobb/ Durham University