““Most of the infectious diseases have now Most of the infectious diseases have now yielded yielded up their secrets. Many illnesses have been up their secrets. Many illnesses have been completely exterminated”.......Dr. Henry completely exterminated”.......Dr. Henry Sigerist (1931)Sigerist (1931)

““It is time to close the book on infectious It is time to close the book on infectious diseases”diseases”

Surgeon General William Stewart Surgeon General William Stewart (1969)-(1969)- speaking before Congress.speaking before Congress.

The OptimistsThe Optimists

Leading Causes of Death in USLeading Causes of Death in US

Bio-TerrorismWMDs

Weapons of mass destruction from our environment: 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 centuryPandemics during the 20th century

1918-1919: “Spanish flu” “La Grippe”(H1N1)1918-1919: “Spanish flu” “La Grippe”(H1N1) deaths 675,000 US, 50 million worldwidedeaths 675,000 US, 50 million worldwide worst natural disaster in recorded historyworst natural disaster in recorded history

1957-1958: “Asian flu” (H2N2)1957-1958: “Asian flu” (H2N2) deaths 70,000 in USdeaths 70,000 in US

1968-1969: “Hong Kong flu” (H3N2)1968-1969: “Hong Kong flu” (H3N2) deaths 34,000 in USdeaths 34,000 in US

note: estimated 36,000 deaths per year from non-note: estimated 36,000 deaths per year from non-pandemic seasonal influenzapandemic 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

Ring around the rosyA pocketful of posies"Ashes, Ashes"We all fall down!

Nursery RhymesNursery Rhymes

Bubonic Plague 1665Bubonic Plague 1665 1918 flu1918 fluI had a little birdI had a little bird

Its name was EnzaIts name was Enza

I opened the windowI opened the window

And in-flu-enzaAnd in-flu-enza

H5N1H5N1

bird flu: has decimated the bird flu: has decimated the domestic bird populations in domestic bird populations in Southeast Asia and has Southeast Asia and has spread to other countries spread to other countries including Turkey, Russia, including Turkey, Russia, Romania.Romania.

As of Oct. 2007: has As of Oct. 2007: has infected only 331 people infected only 331 people with 203 deathswith 203 deaths

Is this the likely candidate Is this the likely candidate for the next pandemic?for the next pandemic?

Genetic reassortment likely to Genetic reassortment likely to occur in pigsoccur in pigs

China 1968China 1968 790 million humans790 million humans 5.2 million pigs5.2 million pigs 12.3 million poultry12.3 million poultry

China 2006China 2006 1300 million humans1300 million humans 508 million pigs508 million pigs 13000 million poultry13000 million poultry

Immune response to Immune response to viral infection causes viral infection causes cytokine release and cytokine release and

leads to acute leads to acute respiratory distress respiratory distress syndrome (ARDS)syndrome (ARDS)

Drug therapyDrug therapy

RocheAmantadine, 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

OTC drugs containing amantadine in Asia OTC drugs containing amantadine in Asia help lead to resistancehelp lead to resistance

Are we prepared for this?Are we prepared for this?

world population is now 6.5 billion (3 times what it was world population is now 6.5 billion (3 times what it was in 1918).in 1918).

requires 350 million chicken eggs and 6 months to requires 350 million chicken eggs and 6 months to make enough vaccine for 500 million make enough vaccine for 500 million (14% of population)(14% of population)

GlaxoSmithKline recently announced a potent combination of antigen and GlaxoSmithKline recently announced a potent combination of antigen and adjuvant that gave strong immunity against H5N1 in a small human trialadjuvant that gave strong immunity against H5N1 in a small human trial

only 105,000 mechanical ventilators in USonly 105,000 mechanical ventilators in US health care workers likely to become ill at increased health care workers likely to become ill at increased

rates compared to general populationrates compared to general population estimates run as high as 1.7 million deaths in US if estimates run as high as 1.7 million deaths in US if

pandemic similar to 1918 in severitypandemic similar to 1918 in severity

Lecture ObjectivesLecture Objectives

1. selective toxicity1. selective toxicity mech. of therapeutic actionmech. of therapeutic action mech. of toxicitymech. of toxicity

2. absorption, metabolism, distribution, excretion2. absorption, metabolism, distribution, excretion

3. resistance: intrinsic and acquired3. resistance: intrinsic and acquired

4. new developments that will lead to more effective 4. new developments that will lead to more effective therapiestherapies

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.ceftriazone

rifampin

pyrazinamide

linezolid

isoniazid

gentamycinerythromycin

doxycycline

cycloserine

clindamycin

ciprofloxacin

chloramphenicol

cefaclor

vancomycin

sulfamethoxazole

quinupristin/dalfopristin

trimethoprim

Protein SynthesisProtein Synthesis

Cell Wall Synthesis

Folic Acid Pathway

RNA Synthesis

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

DNA Gyrase

How do antibiotics kill bacteria?How do antibiotics kill bacteria?

cell wall inhibitors (cell wall inhibitors (-lactams), topoisomerase -lactams), topoisomerase inhibitors (ciprofloxacin), and protein synthesis inhibitors (ciprofloxacin), and protein synthesis inhibitors (aminoglycosides) have completely inhibitors (aminoglycosides) have completely different cellular targetsdifferent cellular targets

is there a common pathway to cell death?is there a common pathway to cell death? differences between differences between bacteriocidalbacteriocidal versus versus

bacteriostaticbacteriostatic? ?

More details on Antibiotic More details on Antibiotic Mechanism of ActionMechanism of Action

Cell Wall Inhibitors:Cell Wall Inhibitors:

1.1. formation of peptidoglycan precursorformation of peptidoglycan precursor• cycloserinecycloserine

2.2. transfer of precursor to cell walltransfer of precursor to cell wall• vancomycin/bacitracinvancomycin/bacitracin

3.3. cross-linking and other modificationscross-linking and other modifications• penicillins, cephalosporins, other penicillins, cephalosporins, other -lactams-lactams

Steps in peptidoglycan cell wall synthesisSteps in peptidoglycan cell wall synthesis

Basic mechanisms to target Basic mechanisms to target peptidoglycan cell wall synthesispeptidoglycan cell wall synthesis

1.1. inhibit D-ala:D-ala formationinhibit D-ala:D-ala formation

2.2. bind to D-ala:D-alabind to D-ala:D-ala

3.3. masquerade as D-ala:D-alamasquerade as D-ala:D-ala

Cycloserine resembles D-Alanine

Vancomycin binds to Dala-Dala and inhibits transfer of phospholipid peptidoglycanprecursor to site of cell wall formation

Penicillin looks likeD-ala--Dala

Covalent attachment of penicillin to transpeptidase

Mycobacterium tuberculosis cell envelopeMycobacterium tuberculosis cell envelope

Synthesis inhibitedSynthesis inhibitedby isoniazid andby isoniazid andpyrazinamidepyrazinamide

Potential new cell wall/membrane Potential new cell wall/membrane inhibitorinhibitor

PlatensimycinPlatensimycin inhibits essential subunit (FabF) of bacterial fatty inhibits essential subunit (FabF) of bacterial fatty

acid synthetase (FASII) in gramacid synthetase (FASII) in gram++ (e.g. Staph) (e.g. Staph) from Streptomyces platensis in soil sample from from Streptomyces platensis in soil sample from

South AfricaSouth Africa eradicates MRSA (methicillin resistant Staph A), eradicates MRSA (methicillin resistant Staph A),

VRSA (vancomycin resistant Staph A)VRSA (vancomycin resistant Staph A) will Merck bring it to market?will Merck bring it to market?