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Healed by a crocodile: The
search for new antibiotics.
TEDx GMU
Monique van Hoek
Associate Professor
School of Systems Biology
George Mason University
We need new antibiotics.
 Rampant Antibiotic Resistant Infections emerging globally.
 Common infections becoming untreatable.
We need new antibiotics.
 Very few new antibiotics in the drug development pipeline.
 Entering the Dark Ages of antibiotic resistance.
We need new antibiotics.
 Resurgence of “old” infections: Tuberculosis – a modern plague
Lest we forget…
 June of 1924 a young man
developed a blister on his toe while
playing tennis.
 A week later he was dead from a
bacterial infection.
 The young man was President
Calvin Coolidge's son.
 When he heard the news, Coolidge
wept and asked what was "the
power and the glory of the
presidency" worth if he could not
prevent the death of his son from a
simple blister?
 That is the world we are heading
back to…
Calvin Jr., Calvin Sr., Grace, and John Coolidge, and their dog. This
photo was taken on the same day that Calvin Jr. got a blister while
playing tennis and later died from the infection.
http://2.bp.blogspot.com/Uh_R1A3vO6M/TlBa_fUoNsI/AAAAAAAAEtg/dsx4BotDt_M/s400/004b13cea00423b3.j
pg
The “Dark Ages”
•
•
•
•
4 y.o. girl in excellent health suddenly developed facial skin infection
Spread relentlessly, fever to 104F
Could not sleep because her face and neck so swollen she could not swallow
her own saliva
Began gasping for breath
Herrell. 1943. Proc Staff Meetings Mayo Clinic 18:65-76
On arrival
to the
hospital
On arrival
to the
hospital
After 14
days of
penicillin
“Moribund”
(on the
verge of
death)
Totally
fine…
Antibiotics: A Global Resource
in Need of Protection
 Prior generations of scientists gave us the gift of antibiotics
 Today, we have to ensure this global treasure is available for our
children and future generations.
Infectious Diseases Society of America campaign
Where can we find new antibiotics?
Two types of immunity
“Specific” immunity
 based on antibodies.
 (for example, vaccines).
 Takes 21 days to develop.
 Very focused on one
microbe (such as this year’s
flu shot).
“Innate” immunity
 “broad-spectrum” general
protection.
 Not specific to one microbe.
 Not based on antibodies.
 Keeps you alive for the 21
days until Specific Immunity
kicks in.
How does innate immunity work?
 Partly through Antimicrobial Peptides.
 Very small proteins that can kill bacteria.
 Made by most higher organisms.
Structural classes of
antimicrobial peptides.
(A) Mixed structure of human βdefensin-2
(B) looped thanatin
(C) β-sheeted polyphemusin
(D) rabbit kidney defensin-1
(E) α-helical magainin-2
(F) extended indolicidin.
Jenssen H et al.
Clin. Microbiol. Rev.
2006;19:491-511
http://cmr.asm.org/content/19/3/491/F1.large.jpg
Antimicrobial peptides kill bacteria.
Antimicrobial
Peptide
Bacteria
Surface
Bacteria make biofilm
 What is Biofilm?
 Resistance Cloak for Bacteria.
 Protects them against antibiotics & your immune system.
 80% of bacterial infections may be biofilm mediated.
http://7bigspoons.com/wp-content/uploads/2012/05/Bacteria-wearing-an-acid-resistant-rain-coat.png
R
Rel
0.4
0.2
We
0
0.4
0.2
0
can make “anti-biofilm”
0
2
1.5
0.5
LL-37 (µM)
antimicrobial
peptides
b2
0
1.5
0.5
0.2
Control
Control
LL-37-treated
35
30
35
30
25
20
15
10
5
0
d
Untreated
60
LL-37
Maximum thickness (µm)
40
d
40
ickness (µm)
Biomass (µm3/µm2)
c
(µm3/µm2)
LL-37-treated
LL-37 (µM)
b
c
0.2
60
50
40
30
20
10
0
Untreated
LL-37
50
40
Natural and synthetic cathelicidin peptides with anti-microbial and anti-biofilm activity against Staphylococcus aureus. Dean SN, Bishop BM, van Hoek
ML. BMC Microbiol. 2011 May 23;11:114.
Susceptibility of Pseudomonas aeruginosa Biofilm to Alpha-Helical Peptides: D-enantiomer of LL-37. Dean SN, Bishop BM, van Hoek ML. Front
Microbiol. 2011;2:128.
25
20
30
Where else can we find new antibiotics?
We can take antimicrobial peptides
and make them better
Naja atra, the Chinese cobra
Naja atra
CATHELICIDN
NA-CATH:
ATRA1-ATRA1
Atra-1
Atra-1
Atra-2
Atra-1
Antimicrobial activity of the Naja atra cathelicidin and related small peptides. de Latour FA, Amer LS, Papanstasiou EA,
Bishop BM, van Hoek ML. Biochem Biophys Res Commun. 2010 Jun 11;396(4):825-30.
Crocodiles & Alligators
Why crocodiles?
Seem resistant to skin/wound
infection, despite living in swamps.
Evolutionarily ancient
 have had millennia to select the
best ways of fighting off
infection.
Crocodile/Alligator Blood is known
to have antimicrobial properties.
The genome is not sequenced yet.
Attempts have been made to find
antimicrobial peptides – mostly
unsuccessful.
How to purify an antimicrobial peptide.
One precious tube
of alligator or
crocodile blood.
Now what?
http://img1.etsystatic.com/005/0/6998440/il_fullxfull.372374857_mn7m.jpg
BioProspecting: A new way to
purify an antimicrobial peptide
 obtain antimicrobial peptides from
many kinds of natural samples.
 Blood, urine, saliva, etc.
 “Bio-prospecting”.
 quickly capture new antimicrobial
peptides from samples
 use advanced modern biochemical
technologies
 Nanomaterials & Nanoparticles
 Advanced Mass Spectrometry to
identify antimicrobial peptides.
http://images1.wikia.nocookie.net/__cb20110901171834/minecraft-tutorials/images/7/72/5995531-1-.jpg
BioProspecting
Recover
particle w/
harvested
peptides.
Large Volume
Complex Sample
(eg Crocodile Blood)
Small peptides trapped
(and protected)
Sieving Shell
Binding core
BioProspector Particle
Concentrated,
Isolated
Peptides
New Crocodile Peptide
 Using multiple techniques, we identified a new Crocodile
Antimicrobial peptide.
 We called it “CHOMP”
 It kills lots of different bad bacteria in the lab.
 It is similar, but not identical, to a known “class” of antimicrobial
peptides.
http://ars.els-cdn.com/content/image/1-s2.0-S1074552110004813-gr1.jpg
Our Dream….
“CROCOSILLIN”
Summary:
 It is critical to conserve antibiotics as a precious resource.
 We have to work urgently to develop new antibiotics.
 We have to be creative in how we find new antibiotics.
http://blogs.smithsonianmag.com/science/files/2011/07/crocodile_smile.jpg
Recent Publications
Acknowledgements
 Scott Dean
 Frank Delatour
 Stephanie Barksdale
 Myung Chung
 Collaborators:
 Dr. Barney Bishop, Department of Chemistry, George Mason
University
 Dr. Joel Schnur, College of Science, George Mason
University
 Funding: DTRA “Translational Peptides for Personnel
Protection”