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Dr. Alvin Fox Antibiotics affecting the cell envelope
Key Words Sterilization/disinfection/antisepsis   Vancomycin Antibiotic   beta lactam Selective toxicity   Penicillins Bac...
STERILIZATION <ul><li>All killed </li></ul><ul><li>non-selective  </li></ul>
Sterilization <ul><li>autoclaving </li></ul><ul><ul><li>121 o C (heat/pressure) </li></ul></ul><ul><ul><ul><ul><li>Heat re...
Membrane filters pores bacteria
Disinfection   <ul><li>Liquids that kill bacteria </li></ul><ul><ul><li>e.g. phenol based </li></ul></ul><ul><ul><li>too t...
Antiseptics <ul><li>Topical (e.g. skin)  </li></ul><ul><ul><li>e.g. iodine or 70% alcohol </li></ul></ul><ul><ul><li>“ red...
ANTIBIOTICS <ul><li>Selectively toxic for bacteria </li></ul><ul><ul><li>bactericidal (killing)  </li></ul></ul><ul><ul><l...
Antibiotics <ul><li>destroy structures </li></ul><ul><ul><li>present in bacteria </li></ul></ul><ul><ul><li>not present in...
Antibiotics work together with immune system
Minimal inhibitory concentration <ul><li>lowest level stopping growth </li></ul><ul><li>e. g. zone of inhibition around a ...
<ul><li>Antibiotics that inhibit cell wall  </li></ul><ul><li>biosynthesis are bactericidal </li></ul><ul><li>Without cell...
Cross-linking of peptidoglycan Old  New
Peptidoglycan synthesis Cytoplasm   Cell wall undecaprenol sugar amino acid Cell Membrane
Cycloserine <ul><ul><li>alanine (ala) analog  </li></ul></ul><ul><ul><li>inhibits conversion of L-ala to D-ala  </li></ul>...
Cycloserine Analog of alanine X Cytoplasm   sugar amino acid X X X
Bacitracin <ul><li>Inhibits dephosphorylation </li></ul>
TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P P Cell wall
TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P Cell wall P
TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P P Cell wall
TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P P Cell wall
TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P P Cell wall
MINUS   BACITRACIN Cell   membrane undecaprenol P Cell wall TRANSPORT OF  PEPTIGOGLYCAN SUBUNIT  ACROSS MEMBRANE
PLUS   Bacitracin Cell membrane undecaprenol P P Cell wall TRANSPORT OF  PEPTIGOGLYCAN SUBUNIT  ACROSS MEMBRANE
Vancomycin Cell wall <ul><li>binds to D-ala-D-ala </li></ul><ul><li>inhibits cross-linking </li></ul>Vancomycin
Beta lactam antibiotics <ul><li>penicillins  </li></ul><ul><li>Cephalosporins/cephamycins  </li></ul><ul><li>monobactams <...
Beta lactams Cell  wall Penicillin binding protein <ul><li>inhibit penicillin binding proteins </li></ul><ul><li>stop cros...
Site of penicillinase action. Breakage of the    lactam ring. STRUCTURE OF PENICILLIN C NH CH CH C O O C N CH CH 3 CH 3 C...
Attached to lactam ring <ul><li>penicillins  </li></ul><ul><ul><li>5 membered ring  </li></ul></ul><ul><li>Cephalosporins/...
Chemical modifications change biological activity <ul><li>Early lactam antibiotics  </li></ul><ul><ul><li>inactive against...
Resistance mechansims <ul><li>Produce beta lactamase (penicillinase) </li></ul><ul><ul><li>destroys antibiotic </li></ul><...
<ul><li>beta lactam  </li></ul><ul><li>binds strongly beta lactamases  </li></ul><ul><ul><li>inhibits activity </li></ul><...
Polymyxin B <ul><li>binds </li></ul><ul><ul><li>lipid A  </li></ul></ul><ul><ul><li>phospholipids </li></ul></ul><ul><li>d...
Isoniazid, Ethambutol, Ethionamide    Isoniazid and Ethionamide  - chemically related -  blocks mycolic acid synthesis Eth...
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  1. 1. Dr. Alvin Fox Antibiotics affecting the cell envelope
  2. 2. Key Words Sterilization/disinfection/antisepsis Vancomycin Antibiotic beta lactam Selective toxicity Penicillins Bactericidal Cephalosporins/cephamycins Bacteriostatic Monobactam Minimal inhibitory concentration (MIC) Clavulinic acid Susceptibility testing Polymyxin B Penicillin binding proteins Isoniazid Penicillinase/beta lactamase Ethioniamide Autolysins Ethambutol Cycloserine Resistance Bacitracin
  3. 3. STERILIZATION <ul><li>All killed </li></ul><ul><li>non-selective </li></ul>
  4. 4. Sterilization <ul><li>autoclaving </li></ul><ul><ul><li>121 o C (heat/pressure) </li></ul></ul><ul><ul><ul><ul><li>Heat resistant materials </li></ul></ul></ul></ul><ul><li>ethylene oxide </li></ul><ul><ul><li>non heat resistant </li></ul></ul><ul><ul><li>Usually equipment </li></ul></ul><ul><ul><li>being replaced e.g. H 2 O 2 /free radicals </li></ul></ul><ul><li>ultra-violet light </li></ul><ul><ul><li>surfaces (e.g operating rooms) </li></ul></ul><ul><ul><li>not totally effective </li></ul></ul><ul><li>gamma radiation </li></ul><ul><ul><li>food </li></ul></ul><ul><ul><li>some mail </li></ul></ul>
  5. 5. Membrane filters pores bacteria
  6. 6. Disinfection <ul><li>Liquids that kill bacteria </li></ul><ul><ul><li>e.g. phenol based </li></ul></ul><ul><ul><li>too toxic for skin surfaces </li></ul></ul>
  7. 7. Antiseptics <ul><li>Topical (e.g. skin) </li></ul><ul><ul><li>e.g. iodine or 70% alcohol </li></ul></ul><ul><ul><li>“ reduce” bacterial load </li></ul></ul>
  8. 8. ANTIBIOTICS <ul><li>Selectively toxic for bacteria </li></ul><ul><ul><li>bactericidal (killing) </li></ul></ul><ul><ul><li>bacteriostatic (growth inhibition) </li></ul></ul><ul><li>no harm to patient </li></ul>
  9. 9. Antibiotics <ul><li>destroy structures </li></ul><ul><ul><li>present in bacteria </li></ul></ul><ul><ul><li>not present in host </li></ul></ul>
  10. 10. Antibiotics work together with immune system
  11. 11. Minimal inhibitory concentration <ul><li>lowest level stopping growth </li></ul><ul><li>e. g. zone of inhibition around a disk impregnated with antibiotic </li></ul>
  12. 12. <ul><li>Antibiotics that inhibit cell wall </li></ul><ul><li>biosynthesis are bactericidal </li></ul><ul><li>Without cell wall, osmotic pressure </li></ul><ul><li>causes bacteria to burst </li></ul>
  13. 13. Cross-linking of peptidoglycan Old New
  14. 14. Peptidoglycan synthesis Cytoplasm Cell wall undecaprenol sugar amino acid Cell Membrane
  15. 15. Cycloserine <ul><ul><li>alanine (ala) analog </li></ul></ul><ul><ul><li>inhibits conversion of L-ala to D-ala </li></ul></ul><ul><ul><li>inhibits formation of D-ala-D-ala </li></ul></ul>
  16. 16. Cycloserine Analog of alanine X Cytoplasm sugar amino acid X X X
  17. 17. Bacitracin <ul><li>Inhibits dephosphorylation </li></ul>
  18. 18. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P P Cell wall
  19. 19. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P Cell wall P
  20. 20. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P P Cell wall
  21. 21. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P P Cell wall
  22. 22. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P P Cell wall
  23. 23. MINUS BACITRACIN Cell membrane undecaprenol P Cell wall TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
  24. 24. PLUS Bacitracin Cell membrane undecaprenol P P Cell wall TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
  25. 25. Vancomycin Cell wall <ul><li>binds to D-ala-D-ala </li></ul><ul><li>inhibits cross-linking </li></ul>Vancomycin
  26. 26. Beta lactam antibiotics <ul><li>penicillins </li></ul><ul><li>Cephalosporins/cephamycins </li></ul><ul><li>monobactams </li></ul>
  27. 27. Beta lactams Cell wall Penicillin binding protein <ul><li>inhibit penicillin binding proteins </li></ul><ul><li>stop cross-linking </li></ul>Beta lactam
  28. 28. Site of penicillinase action. Breakage of the  lactam ring. STRUCTURE OF PENICILLIN C NH CH CH C O O C N CH CH 3 CH 3 COOH S
  29. 29. Attached to lactam ring <ul><li>penicillins </li></ul><ul><ul><li>5 membered ring </li></ul></ul><ul><li>Cephalosporins/cephamycins </li></ul><ul><ul><li>6 membered ring </li></ul></ul><ul><li>monobactams </li></ul><ul><ul><li>no second ring </li></ul></ul>
  30. 30. Chemical modifications change biological activity <ul><li>Early lactam antibiotics </li></ul><ul><ul><li>inactive against Gram negative bacteria </li></ul></ul><ul><li>no penetration of outer membrane </li></ul>
  31. 31. Resistance mechansims <ul><li>Produce beta lactamase (penicillinase) </li></ul><ul><ul><li>destroys antibiotic </li></ul></ul><ul><li>modified penicillin binding proteins </li></ul><ul><ul><li>don’t bind antibiotic </li></ul></ul><ul><li>modified porins </li></ul><ul><ul><li>no internalization of antibiotic </li></ul></ul>
  32. 32. <ul><li>beta lactam </li></ul><ul><li>binds strongly beta lactamases </li></ul><ul><ul><li>inhibits activity </li></ul></ul>Clavulinic acid
  33. 33. Polymyxin B <ul><li>binds </li></ul><ul><ul><li>lipid A </li></ul></ul><ul><ul><li>phospholipids </li></ul></ul><ul><li>disrupts outer membrane, Gram negative bacteria </li></ul><ul><li>toxic to human cells </li></ul>
  34. 34. Isoniazid, Ethambutol, Ethionamide   Isoniazid and Ethionamide - chemically related - blocks mycolic acid synthesis Ethambutol - blocks arabinogalactan synthesis Anti-tuberculosis drugs

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