The evolution of antimicrobial resistance: a Darwinian perspective

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Sir Richard Sykes presented this Friday Evening Discourse at the Royal Institution of Great Britain on Friday 6 May 2011.

Microbes have evolved over 3.5 billion years and are arguably the most adaptable organisms on earth. Restricted genetically by their inability to reproduce sexually, bacteria have acquired several additional mechanisms by which to exchange genetic material. Such mechanisms have allowed bacteria to inhabit some of the most inhospitable environments on earth. It is then hardly surprising that when faced with a barrage of inimical chemicals (antibiotics) they have responded with an equal and opposite force.

Sir Richard compared and contrasted the evolution of antimicrobial resistance to B-lactam antibiotics over the last 70 years in two bacterial species, namely Staphylococcus aureus, a highly evolved human pathogen, and Pseudomonas aeruginosa, an opportunistic nosocomial pathogen.

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The evolution of antimicrobial resistance: a Darwinian perspective

  1. 1. Sir Richard Sykes, FRS <ul><li>The Evolution of Antimicrobial Resistance: A Darwinian Perspective </li></ul>
  2. 2.
  3. 3.
  4. 4.
  5. 5.
  6. 6. Meiosis
  7. 7. Binary fission
  8. 8. Deep sea vent
  9. 9. Major mechanisms of genetic transfer <ul><li>Transformation Uptake of naked DNA </li></ul><ul><li>Transduction Transfer of DNA by </li></ul><ul><li>phage </li></ul><ul><li>Congugation Transfer of DNA by cell </li></ul><ul><li>to cell contact </li></ul>
  10. 10. Plasmid <ul><li>Plasmids are extra-chromosomal circular double standard DNA molecules separate from chromosomal DNA capable of replicating independently of chromosomal DNA. </li></ul><ul><li>Host to host transfer requires direct mechanical transfer by conjugation or uptake by transduction. </li></ul>
  11. 11. Transposon <ul><li>Transposons, or jumping genes, are sequences of DNA that can move around to different positions within the genome of a single cell (transposition). </li></ul><ul><li>They can jump from chromosome DNA to plasmid DNA and back, a good mechanism for developing multi resistant strains and causing mutations. </li></ul>
  12. 12. Integron <ul><li>Integron: The integron is a gene capture system found in plasmids, chromosomes and transposons. </li></ul><ul><li>Pieces of DNA called gene cassettes can be incorporated expressed and disseminated. </li></ul>
  13. 13. Conjugating bacteria
  14. 14. Staphylococcus aureus
  15. 15. Mechanism of antibiotic action <ul><li>Antibiotic Target (s) Cell Response </li></ul><ul><li>Amount Nature of Nature </li></ul><ul><li>Reaching Target of </li></ul><ul><li>Target Response </li></ul>
  16. 16. Gram positive cell wall Carboxypeptidase Transpeptidase
  17. 17. 1 Penicillin sensitive enzymes, involved in cell wall biosynthesis GlcNAc MurNAc GlcNAc MurNAc GlcNAc MurNAc L - Ala D - Glu meso - DAP D - Ala L - Ala D - Glu meso - DAP - ? - NH 2 D - Ala L - Ala D - Glu meso - DAP D - Ala D - Ala DD - Carboxypeptidase LD - Carboxypeptdase D - Ala meso - DAP D - Glu L - Ala MurNAc D - Ala meso - DAP D - Glu L - Ala MurNAc GlcNAc GlcNAc Transpeptidase
  18. 18. Structure of cell wall peptide and pencillin
  19. 19. Mechanism of antibiotic action <ul><li>Antibiotic Target (s) Cell Response </li></ul><ul><li>Amount Nature of Nature </li></ul><ul><li>Reaching Target of </li></ul><ul><li>Target Response </li></ul>
  20. 20. Gram positive cell wall . .
  21. 21. Inactivation of Penicillin by B- Lactamase
  22. 22. Bacteriophage
  23. 23. Gram positive cell wall Transpeptidase B-lactamase
  24. 24. Bacterial Plasmids
  25. 25. Semi synthetic penicillins 6-APA Methicillin Cloxacillin
  26. 26.
  27. 27. Necrotising Fascilitis
  28. 28. Gram positive cell wall Transpeptidase B-lactamase
  29. 29. Cephalasporin C – 7-ACA (capital c) Cephalosporin C 7- Aminocephalosporanic acid (7-ACA)
  30. 30. Cephalothin and Cephaloridine <ul><li>Cephalothin </li></ul><ul><li>Cephaloridine </li></ul>
  31. 31. Clavulanic acid
  32. 32. The mechanisms of antibiotic resistance in staphylococci <ul><li>Enzymatic inactivation : β-lactams and </li></ul><ul><li>aminoglycosides </li></ul><ul><li>Alteration of target: methicillin, macrolides, </li></ul><ul><li>vancomycin </li></ul><ul><li>Antibiotic trapping: vancomycin and daptomycin </li></ul><ul><li></li></ul>
  33. 33. Pseudomonas aeruginosa
  34. 34. Pseudomonas infection
  35. 35. Pseudomonas cell wall B-lactamase Transpeptidase
  36. 36. Efflux Systems in Pseudomonas <ul><li>An energy dependent pump </li></ul><ul><li>An outer membrane porin </li></ul><ul><li>A linker protein which couples the two membrane proteins together </li></ul><ul><li></li></ul>
  37. 37. Antibiotic efflux Efflux Pump
  38. 38. Pseudomonas cell wall B-lactamase Transpeptidase
  39. 39. Carbenicillin
  40. 40. Ceftazidine
  41. 41. Thienamycin - imipenem <ul><li>Thienamycin </li></ul><ul><li>Imipenem </li></ul>
  42. 42. Monobactams <ul><li>Aztreonam </li></ul><ul><li>Monobactam </li></ul>
  43. 43. Number of Discrete β -lactamases Identified <ul><li>1972 - 13 </li></ul><ul><li>1999 - 282 </li></ul><ul><li>2004 - 532 </li></ul><ul><li>2010 - >950 </li></ul>OXA-48. Docquier et al., Chem. Biol. 16:540, 2009
  44. 44. β -lactamases of Pseudomonas <ul><li>CLASS </li></ul><ul><li>A Carbenicillinases (PSE) </li></ul><ul><li>Extended spectrum β -lactamases (ESBL) </li></ul><ul><li>B Metallo β -lactamases </li></ul><ul><li>C Cephalosporinases </li></ul><ul><li>D Oxacillinases </li></ul><ul><li></li></ul>
  45. 45. Class A β-lactamases <ul><li>PSE 1-4 – Transposon mediated </li></ul><ul><li>ESBL – TEM type </li></ul><ul><li>SHVs </li></ul><ul><li>PER </li></ul><ul><li>VeB </li></ul><ul><li>GES </li></ul><ul><li>Dissemination by plasmids and integrons </li></ul><ul><li></li></ul>
  46. 46. Class B β -lactamases <ul><li>Metallo β -lactamases </li></ul><ul><li>Carbapenemases </li></ul><ul><li>VIM </li></ul><ul><li>IMP </li></ul><ul><li>GIM </li></ul><ul><li>SIM </li></ul><ul><li>SPM – gene cassettes and integrons and transposons </li></ul>
  47. 47. Class C β -lactamases <ul><li>Cephalosporinases </li></ul><ul><li>AmpC gene </li></ul>
  48. 48. Class D β -lactamases <ul><li>Oxacillinases </li></ul><ul><li>5 groups Chromosomal </li></ul><ul><li>Plasmid mediated </li></ul><ul><li>Integron </li></ul>
  49. 49. Number of Discrete β -lactamases Identified <ul><li>1972 - 13 </li></ul><ul><li>1999 - 282 </li></ul><ul><li>2004 - 532 </li></ul><ul><li>2010 - >950 </li></ul>OXA-48. Docquier et al., Chem. Biol. 16:540, 2009
  50. 50. Mechanisms of Resistance <ul><li>1. Enzymatic inactivation </li></ul><ul><li> β -lactams </li></ul><ul><li>Aminoglycosides </li></ul><ul><li>2. Efflux mechanisms effective against all antibiotics </li></ul><ul><li>3. Alteration of target site </li></ul><ul><li>Aminoglycosides </li></ul><ul><li>Fluroquinolones </li></ul><ul><li>4. Porin exclusion </li></ul><ul><li>Carbapenems </li></ul>

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