1. “Most of the infectious diseases have now yielded up their secrets. Many illnesses have been completely exterminated”.......Dr. Henry Sigerist (1931) “It is time to close the book on infectious diseases” Surgeon General William Stewart (1969)- speaking before Congress. The Optimists

2. Leading Causes of Death in US

5. Bio-Terrorism WMDs

6. Weapons of mass destruction from our environment:

7. Influenza replication From Medical Microbiology, 5 th ed., Murray, Rosenthal & Pfaller, Mosby Inc., 2005, Figure 60-2.

8. Pandemics during the 20th century  1918-1919: “Spanish flu” “La Grippe”(H1N1) deaths 675,000 US, 50 million worldwide deaths 675,000 US, 50 million worldwide worst natural disaster in recorded history worst natural disaster in recorded history  1957-1958: “Asian flu” (H2N2) deaths 70,000 in US deaths 70,000 in US  1968-1969: “Hong Kong flu” (H3N2) deaths 34,000 in US deaths 34,000 in US  note: estimated 36,000 deaths per year from non- pandemic seasonal influenza

9. The 1918 Spanish flu pandemic National Museum of Health and Medicine, Armed Forces Institute of Pathology

10. Images from the 1918 Influenza Epidemic National Museum of Heath and Medicine

11. Ring around the rosy A pocketful of posies "Ashes, Ashes" We all fall down! Nursery Rhymes  Bubonic Plague 1665  1918 flu I had a little bird Its name was Enza I opened the window And in-flu-enza

12. H5N1  bird flu: has decimated the domestic bird populations in Southeast Asia and has spread to other countries including Turkey, Russia, Romania.  As of Oct. 2007: has infected only 331 people with 203 deaths  Is this the likely candidate for the next pandemic?

15. Genetic reassortment likely to occur in pigs  China 1968 790 million humans 790 million humans 5.2 million pigs 5.2 million pigs 12.3 million poultry 12.3 million poultry  China 2006 1300 million humans 508 million pigs 13000 million poultry

16. Immune response to viral infection causes cytokine release and leads to acute respiratory distress syndrome (ARDS)

17. Drug therapy Roche Amantadine, rimantadine block viral M2 ion channel required for viral uncoating in cell Oseltamivir (TAMIFLU), zanamivir (RELENZA) neuraminidase inhibitors, prevents release of virus from infected cell

19. OTC drugs containing amantadine in Asia help lead to resistance

20. Are we prepared for this?  world population is now 6.5 billion (3 times what it was in 1918).  requires 350 million chicken eggs and 6 months to make enough vaccine for 500 million (14% of population) GlaxoSmithKline recently announced a potent combination of antigen and adjuvant that gave strong immunity against H5N1 in a small human trial GlaxoSmithKline recently announced a potent combination of antigen and adjuvant that gave strong immunity against H5N1 in a small human trial  only 105,000 mechanical ventilators in US  health care workers likely to become ill at increased rates compared to general population  estimates run as high as 1.7 million deaths in US if pandemic similar to 1918 in severity

21. Lecture Objectives 1. selective toxicity mech. of therapeutic action mech. of therapeutic action mech. of toxicity mech. of toxicity 2. absorption, metabolism, distribution, excretion 3. resistance: intrinsic and acquired 4. new developments that will lead to more effective therapies

22. ceftriazone rifampin pyrazinamide linezolid isoniazid gentamycin erythromycin doxycycline cycloserine clindamycin ciprofloxacin chloramphenicol cefaclor vancomycin sulfamethoxazole quinupristin/dalfopristin trimethoprim Protein Synthesis Cell Wall Synthesis Folic Acid Pathway RNA Synthesis DNA Gyrase

23. How do antibiotics kill bacteria?  cell wall inhibitors (  -lactams), topoisomerase inhibitors (ciprofloxacin), and protein synthesis inhibitors (aminoglycosides) have completely different cellular targets  is there a common pathway to cell death?  differences between bacteriocidal versus bacteriostatic?

26. More details on Antibiotic Mechanism of Action

27. Cell Wall Inhibitors: 1.formation of peptidoglycan precursor cycloserine cycloserine 2.transfer of precursor to cell wall vancomycin/bacitracin vancomycin/bacitracin 3.cross-linking and other modifications penicillins, cephalosporins, other  -lactams penicillins, cephalosporins, other  -lactams Steps in peptidoglycan cell wall synthesis

28. Basic mechanisms to target peptidoglycan cell wall synthesis 1.inhibit D-ala:D-ala formation 2.bind to D-ala:D-ala 3.masquerade as D-ala:D-ala

29. Cycloserine resembles D-Alanine

32. Vancomycin binds to Dala- Dala and inhibits transfer of phospholipid peptidoglycan precursor to site of cell wall formation

33. Penicillin looks like D-ala--Dala

34. Covalent attachment of penicillin to transpeptidase

35. Mycobacterium tuberculosis cell envelope Synthesis inhibited by isoniazid and pyrazinamide

37. Potential new cell wall/membrane inhibitor  Platensimycin inhibits essential subunit (FabF) of bacterial fatty acid synthetase (FASII) in gram + (e.g. Staph) inhibits essential subunit (FabF) of bacterial fatty acid synthetase (FASII) in gram + (e.g. Staph) from Streptomyces platensis in soil sample from South Africa from Streptomyces platensis in soil sample from South Africa eradicates MRSA (methicillin resistant Staph A), VRSA (vancomycin resistant Staph A) eradicates MRSA (methicillin resistant Staph A), VRSA (vancomycin resistant Staph A) will Merck bring it to market? will Merck bring it to market?