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“Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops, into children’s bellies and their bright eyes. Good things don’t get lost.
Here's what I've decided: the very least you can do in your life is to figure out what you hope for. And the most you can do is live inside that hope. Not admire it from a distance but live right inside it, under its roof. What I want is so simple I almost can't say it: elementary kindness. Enough to eat, enough to go around. The possibility that kids might one day grow up to be neither the destroyers nor the destroyed. That's about it. Right now I'm living in that hope, running down its hallway and touching the walls on both sides. I can't tell you how good it feels”
From Barbara Kingsolver, “Animal Dreams”
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Waverly Hills Tuberculosis Sanatorium. Louisville KT 1926
Built in 1911, expanded in 1926, closed in 1961
www.umdnj.edu/librweb
Despite Koch’s discovery, for 60 years the only treatment was isolation, “fresh air, and sunshine”
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So it was time for another Nobel laureate!
Selman Waksman1888-1973
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He was working on bugs that live in dirt!
Selman Waksman1888-1973
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Selman Waksman1888-1973
A childhood immigrant from theUkraine, through hard workHe became a professorOf microbiology and biochemistry at Rutgers
He was working on bugs that live in dirt!
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Selman Waksman1888-1973
A childhood immigrant from theUkraine, through hard workHe became a professorOf microbiology and biochemistry at Rutgers
He coined the term antibiotic andDiscovered more than 20Antibiotics, including two whichAre widely used today.
Neomycin--check your medicine cabinet
He was working on bugs that live in dirt!
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StreptomycinStreptomyces griseus.
He was working on bugs that live in dirt!
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StreptomycinStreptomyces griseus.
Isolated on October 19, 1943 by Albert Schatz, a graduate student in Waksman’s lab
He was working on bugs that live in dirt!
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Streptomycin
Isolated on October 19, 1943 by Albert Schatz, a graduate student in Waksman’s lab
He was working on bugs that live in dirt!
the-scientist.com
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Streptomycin kills many bacteria, including
Mycobacterium Tuberculosis!
Bugs fight bugs
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Streptomycin kills many bacteria, including
Mycobacterium Tuberculosis!
Bugs fight bugs
But how?
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The central dogma--anybody remember that?
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The central dogma--anybody remember that?
DNA -> RNA -> Proteins
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The central dogma--anybody remember that?
DNA -> RNA -> Proteins
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And we call that step?
DNA -> RNA -> Proteins
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Translation!
DNA -> RNA -> Proteins
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www.palaeos.com
Bacteria do it too, and like us they use RIBOSOMES
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Lovely picture from Harry Noller
Let’s zoom in on the action
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Lovely picture from Harry Noller
The ribosome is an amazing machineThat unlike most in the cell runs on RNA!
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Lovely picture from Harry Noller
The ribosome is an amazing machineThat unlike most in the cell runs on RNA!
16S rRNA + proteins =30S or small subunit
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If we zoom in further…
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Lovely picture from Harry Noller
Luckily, our ribosomes are slightly differentand thus streptomycin affects them less
16S rRNA + proteins =30S subunit
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Streptomycin cannot be given orally, but must be administered by regular intramuscular injection.
An adverse effect of this drug is ototoxicity, i.e. It can result in temporary hearing loss.
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Streptomycin cannot be given orally, but must be administered by regular intramuscular injection.
An adverse effect of this drug is ototoxicity, i.e. It can result in temporary hearing loss.
Cool fact--this may be due to effect on Mitochondrial ribosomes!!!
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OK. So streptomycin kills bugs ina flask in the lab. What about inside a patient?
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First we have to make a lot of it.
In steps George Merck
of Merck and Co.
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First we have to make a lot of it.
In steps George Merck
of Merck and Co.
And we got the patent…
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First we have to make a lot of it.
In steps George Merck
of Merck and Co.
But we gave it back to Rutgers!
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Now we need to try it on animals.Enter Dr. William H. Feldman and Dr. H. Corwin Hinshaw at the Mayo Clinic
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Now we need to try it on animals.Enter Dr. William H. Feldman and Dr. H. Corwin Hinshaw at the Mayo Clinic
In two months they reported to Waksman that four tubercular guinea pigs receiving streptomycin "look exceedingly well."
We do, don’t we!
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OK, but how about people?Next Feldman and Hinshaw invent clinical trials
www.jameslindlibrary.org
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OK, but how about people?Next Feldman and Hinshaw invent clinical trials
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OK, but how about people?Next Feldman and Hinshaw invent clinical trials
This is really important!!
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OK, but how about people?
In August 1945 Hinshaw reported that thirty-three patients had been treated "and [we] continue to be quite optimistic."
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Initially streptomycin appeared to be a miracle cure
Patients, including the first, “Patricia T”,Were returned to health from death’s door
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Now the problem was scaling up
(Remember 5 million people a yearWere still dying of TB!)
By 1948 8 companies were making streptomycinBut their 80,000 pounds
Would only treat 1000 patients
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Initially streptomycin appeared to be a miracle cure
BUT…..
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A second, much worse Problem was now on the horizon
By 1948 patients began to relapse!
For example the author George Orwell
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But a second, much worse problem was now on the horizon
In an MRC clinical trial, patients improved rapidlyBut within five years the death rate was the
Same as the untreated controls
Professor Hill of the MRC
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But a second, much worse problem was now on the horizon
In an MRC clinical trial, patients improved rapidlyBut within five years the death rate was the
Same as the untreated controls
Professor Hill of the MRC
Uh, oh.
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What was going wrong??
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Streptomycin resistant bacteriacould be cultured from these patients!
What was going wrong??
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Streptomycin resistant bacteriacould be cultured from these patients!
What was going wrong??
How couldThat happen?
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Streptomycin resistant bacteriacould be cultured from these patients!
What was going wrong??
How couldThat happen?
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Have you heardThe one aboutNatural selection?
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What was going wrong??
evolution.berkeley.edu
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And how did this happen?
evolution.berkeley.edu
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And how did this happen?
evolution.berkeley.edu
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And how did this happen?
evolution.berkeley.edu
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And how did this happen?
evolution.berkeley.edu
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And how did this happen?
Lovely picture from Harry Noller
16S rRNA + proteins =30S subunit
Remember me?
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Occasional bacteria had variants in16sRNA or the ribosomal protein S12
Lovely picture from Harry Noller
16S rRNA + proteins =30S subunit
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These blocked binding of streptomycin to the ribosome and thus these bacteria
were resistant!
Lovely picture from Harry Noller
16S rRNA + proteins =30S subunit
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Thanks and kudos to Gary Trudeau for hitting the nail on the head
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So what now?
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So what now?
Luckily, help was on the wayfrom
para-aminosalycilic acid (PAS)
Jörgen Lehmann
AND
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Lehmann started with a strange published factThe TB bug loves to eat aspirin (salicylic acid)
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Lehmann started with a strange published factThe TB bug loves to eat aspirin (salicylic acid)
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Lehmann started with a strange published factThe TB bug loves to eat aspirin (salicylic acid)
His hypothesis: Alter aspirin slightlyAnd the bugs will die trying to eat it
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Lehmann moved quickly, from bacterial trials in December 1943To Guinea pig trials in January 1944To the first patient in March 1944 (before streptomycin!!)
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Chest 1949;16;684-703
Lehmann J. Para-aminosalicylic acid in the treatment of tuberculosis. Lancet. 1946; 1:15-6.
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So how does PAS work?
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So how does PAS work?
50 years later we still don’t know for sure
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So how does PAS work?
It is likely to act somewhere in the pathwayFor making nucleotides to make DNA
http://themedicalbiochemistrypage.org
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So which is better:Streptomycin or PAS?
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So which is better:Streptomycin or PAS?
BOTH!
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Remember this?
I fear no streptomycin
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Remember this?
I fear no streptomycin
and PAS doesn’t touch me
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I fear no streptomycin
and PAS doesn’t touch me
But if the same patient is given both drugs…
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Ahhhh……
No………
But if the same patient is given both drugs…
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The two drug combination becameThe new standard
After this trial…..
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But the story is not over yet-- we neededAnother Nobel laureate
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Nobelprize.org
I was already the 1939 Nobel laureateFor discovering sulphanilamideThe first antibacterial drug
Gerhard Domagk
But the story is not over yet-- we neededAnother Nobel laureate
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Nobelprize.org
I was already the 1939 Nobel laureateFor discovering sulphanilamideThe first antibacterial drug
Gerhard Domagk
(though I was not allowed by the Nazisto accept the prize and I was held by the Gestapo for a week because of this honor)
But the story is not over yet-- we neededAnother Nobel laureate
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Nobelprize.org
Gerhard Domagk
But the story is not over yet-- we neededAnother Nobel laureate
I spent World War II in a bomb-damaged hospital labpursuing new chemical relatives ofsulphanilamide thatmight be effective against TB
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Here’s what I discovered
Isoniazid
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Here’s what I discovered
Isoniazid
First we need to know moreAbout mycobacteria
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All living cellsHave a plasma membrane
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All living cellsHave a plasma membrane
Gram positiveBacteria alsoHave a cell wall
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All living cellsHave a plasma membrane
Gram positiveBacteria alsoHave a cell wall
Mycobacteria have aVery complex cell wallServing as a barrier
http://web.uct.ac.za/depts/mmi/lsteyn/cellwall.html
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1. outer lipids2. mycolic acid3. polysaccharides (arabinogalactan)4. peptideglycan5. plasma membrane6. lipoarabinomannan (LAM)7. phosphatidylinositol mannoside8. cell wall skeleton
Wikipeda/mycobacterium
Just look at the parts list
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1. outer lipids2. mycolic acid3. polysaccharides (arabinogalactan)4. peptideglycan5. plasma membrane6. lipoarabinomannan (LAM)7. phosphatidylinositol mannoside8. cell wall skeleton
Wikipeda/mycobacterium
Just look at the parts list
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Isoniazid is metabolized by the bacteriumTo isonicotinic acyl anion or radical
and inhibits the enzymethat makes
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Isoniazid was added to the combination therapyand remains there today!
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Isoniazid was added to the combination therapyand remains there today!
Streptomycin and PAS were removed fromfrontline therapy as new drugs
that were more effective orhad fewer side effects
came into the clinic
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National Institute of Allergy and Infectious Diseases (NIAID) 2007
Current first-line TB drugs and their dates of discovery
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NIAID (2007)
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Let’s look at one of the new drugs in detail
rifampicin
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It binds the ß subunit of RNA polymerase
rifampicin
Check out a cool video view athttp://www.pingrysmartteam.com/rifampicin/rifampicin.htm
Cell. 2001 Mar 23;104(6):901-12
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Binding does not block recruitment to the promotorBut inhibits transcription elongation after 2-3 nucleotides are madeby sterically blocking transcript elongation
Cell. 2001 Mar 23;104(6):901-12
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Let’s take a closer look
Cell. 2001 Mar 23;104(6):901-12
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Most mutations that confer rifampicin resistance changeResidues in the binding pocket
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Our RNA polymerase is different enough that it is notinhibited by rifampicin
Cell. 2001 Mar 23;104(6):901-12
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CDC
First-line TB drugs
Left to right isoniazid, rifampin, pyrazinamide, & ethambutol Streptomycin (not shown) is given by injection
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First-line TB drugs
TBAlliance
4 drugs, 130 doses
Over 6-9 months!
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First-line TB drugs
TBAlliance
4 drugs, 130 doses!
http://www.mcvay.com/tb_treatment_in_the_western.html
Daily dose!
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First-line TB drugs
TBAlliance
Are also not compatible withAntiretroviral HIV therapy
(problem for 1/3 of HIV patients!)
Rifampin induces cytochrome p450s, Increasing metabolism of anti-HIV drugs
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Remember the difference in TB rates world-wide but
CDC
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The other major challengeIs multi-drug resistant TB
CDC
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Remember this story???
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In other word MDR TB says
I fear none of theFirst line drugs!
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What drives drug resistance?
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Incorrect, unsupervised, or incomplete treatment
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The answer in the developed world:
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The answer in the developed world:
MORE DRUGS!
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NIAID (2007)
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NIAID (2007)
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New TB drugs under development
NIAID (2007)
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Nature 393, 537-544(11 June 1998)
And the future beckons
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Nature 393, 537-544(11 June 1998)
In 1998 the Sanger centre and the Pasteur InstituteDetermined the complete genome sequence
Of M. tuberculosis
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Nature 393, 537-544(11 June 1998)
4.4 million base pairs
About 4000 genes
Remarkable diversityOf genes involved in fatty acid
Synthesis and metabolism (>250 genes)
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Nature 393, 537-544(11 June 1998)
Remarkable diversityOf genes involved
in fatty acidSynthesis and
metabolism (>250 genes)
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Nature 393, 537-544(11 June 1998)
The genome provides new targets for
drugs and vaccines
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Stats from WHO; slide from TBAlliance
But in the developing world…..