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The Optimists
“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.
Leading Causes of Death in US
Bio-Terrorism
WMDs
Weapons of mass destruction from our environment:
Influenza replication
From Medical Microbiology, 5th ed., Murray, Rosenthal & Pfaller, Mosby Inc., 2005, Figure 60-2.
Pandemics during the 20th century
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1918-1919: “Spanish flu” “La Grippe”(H1N1)
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1957-1958: “Asian flu” (H2N2)
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deaths 70,000 in US
1968-1969: “Hong Kong flu” (H3N2)
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deaths 675,000 US, 50 million worldwide
worst natural disaster in recorded history
deaths 34,000 in US
note: estimated 36,000 deaths per year from nonpandemic seasonal influenza
The 1918 Spanish flu pandemic
National Museum of Health and Medicine, Armed Forces Institute of Pathology
Images from the 1918 Influenza Epidemic
National Museum of Heath and Medicine
Nursery Rhymes

Bubonic Plague 1665
Ring around the rosy
A pocketful of posies
"Ashes, Ashes"
We all fall down!
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1918 flu
I had a little bird
Its name was Enza
I opened the window
And in-flu-enza
H5N1
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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?
Genetic reassortment likely to
occur in pigs
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China 1968
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790 million humans
5.2 million pigs
12.3 million poultry
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China 2006
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1300 million humans
508 million pigs
13000 million poultry
Immune response to
viral infection causes
cytokine release and
leads to acute
respiratory distress
syndrome (ARDS)
Drug therapy
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
Roche
OTC drugs containing amantadine in
Asia help lead to resistance
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
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
Lecture Objectives
1. selective toxicity


mech. of therapeutic action
mech. of toxicity
2. absorption, metabolism, distribution, excretion
3. resistance: intrinsic and acquired
4. new developments that will lead to more effective
therapies
Cell Wall Synthesis
rifampin
sulfamethoxazole
trimethoprim
pyrazinamide
Folic Acid Pathway
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
cycloserine
RNA Synthesis
Protein Synthesis
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
isoniazid
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
DNA Gyrase
ciprofloxacin
cefaclor
vancomycin
chloramphenicol
clindamycin
ceftriazone
doxycycline
quinupristin/dalfopristin
erythromycin
gentamycin
linezolid
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?
More details on Antibiotic
Mechanism of Action
Cell Wall Inhibitors:
Steps in peptidoglycan cell wall synthesis
1.
formation of peptidoglycan precursor
•
cycloserine
•
vancomycin/bacitracin
•
penicillins, cephalosporins, other -lactams
2. transfer of precursor to cell wall
3. cross-linking and other modifications
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
Cycloserine resembles D-Alanine
Vancomycin binds to DalaDala and inhibits transfer of
phospholipid peptidoglycan
precursor to site of cell wall
formation
Penicillin looks like
D-ala--Dala
Covalent attachment of penicillin to transpeptidase
Mycobacterium tuberculosis cell envelope
Synthesis inhibited
by isoniazid and
pyrazinamide
Potential new cell wall/membrane
inhibitor
 Platensimycin
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inhibits essential subunit (FabF) of bacterial fatty
acid synthetase (FASII) in gram+ (e.g. Staph)
from Streptomyces platensis in soil sample from
South Africa
eradicates MRSA (methicillin resistant Staph A),
VRSA (vancomycin resistant Staph A)
will Merck bring it to market?