biologic antimicrobial countermeasures “the enemy of my enemy is my friend*” devon byrd dtra/asx...
TRANSCRIPT
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Biologic Antimicrobial Countermeasures
“The enemy of my enemy is my friend*”
Devon ByrdDTRA/ASX
* usual caveats apply…
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Overview
• Bacteriophage are viruses that specifically destroy bacteria
• They use tricks shared by bacteria that kill other bacteria
• Most higher organisms have ways to kill bacteria• These mechanisms are discoverable and
exploitable• In general, very efficient and man portable
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DECON
Direct Action
Biologic Countermeasures Cut Across Agent Defeat Missions
DISRUPT DEFEAT DESTROY
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Bacteriophage (or phage for short)kill bacteria
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Generic Bacteriophage Structure
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Lytic Phage Replication
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Lysis of bacterial cells by phage (courtesy of Ry Young, TAMU)
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As lytic phage propagate, bacteria are destroyed
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Bacteriophage target many aspects of host microbial metabolism– Can be independently and/or synergistically exploited
Phage produce products that disrupt the following
bacterial systems:• Genome integrity• DNA replication• Gene expression• Protein synthesis• Cellular integrity
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Phage are a paradigm for biologically-based antimicrobial countermeasures
• Bacteria have been in a molecular arms race for billions of years
• They have thoroughly worked out the best ways to kill each other…
• …as have other organisms (innate immunity)• Very rich area for antimicrobial countermeasure
R&D and acquisition
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• Enzymatic– Lysozymes– B-glucosidases– Nucleases– Proteases
• Non-enzymatic– Very effective on microbes (bacteria, viruses, fungi, etc.)– Some evidence effective on spores– Probably not useful for toxins– Bacteriocins- produced by bacteria– Antimicrobial peptides (AMPs)- produced by higher organisms
Categories of antimicrobial proteins
} Bugs
Toxins and spores
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Examples of anti microbial agents that are produced by bacteria
Anti sigma factors
• Inactivate bacterial transcription factors
Toxin/antitoxin systems
• Disrupt various metabolic components
Autolysins
• Programmed cell death
Bacteriocins
• Cell lysis
• Replication
• Protein synthesis
• Gene expression
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Interaction of MccJ25 with RNAP secondary channel: a cork in the bottle
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Non-bacterial Sources
CecropinsThanatinAndroctoninDefensins
MagaininsBombininsCitropins
Arthropods Amphibians
Fish
PardaxinParasinHepcidin
Nematodes
ASABF(Ascaris suum antibacterial factor)
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LocationsGSL
Amazon
CrimeaAzov Sea
Rift Valley
Baikal Region
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Bio-prospecting• Go somewhere (hi/low, hot/cold, wet/dry… it
doesn’t matter- something will live there)
• Acquire indigenous knowledge (if possible)
• Recover specimens from various environments (soil, water, bugs, worms…)
• RTB specimens
• Analyze for useful properties/products
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Potency of selected AMPs
AntimicrobialAgent
Gram(+)
Gram(-)
Amount required to sterilize1000 liters of culture*
Heat/DessicationStable
RH5 Y Y 25 g (0.9 oz) YES
Thanatin Y Y 25 g (0.9 oz) YES
CecropinB N Y 6 g (.02 oz) YES
Hepcidin Y Y 60 g (2.1 oz) YES
Magainin 2 Y Y 10 g (0.4 oz) YES
Temporin F Y Y 14 g (0.5 oz) YES
Synthetic Y Y 5 g (0.1 oz) YES
Phage Y Y 1-1000 particles NO
*NOTE: values are extrapolated from reported data
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Phage Peptides
• Tend to be specific for a given target agent
• Need specific knowledge of target in order to deliver appropriate phage
• …or…• Need to carry all possible
phage for all possible target organisms
• No synergy when combined• Essentially zero weight
• More generic- a properly selected peptide will be effective against a fairly wide range of bacteria
• Exhibit synergistic effects when combined- dramatic increase in potency and target range
• Extremely light weight• Generally heat and desiccation
stable
Phage and peptides can be combined for maximum effect
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Selected Web Resources for antimicrobial peptides
• http://aps.unmc.edu/AP/main.php
• http://www.bbcm.units.it/~tossi/pag1.htm
• http://oma.terkko.helsinki.fi:8080/~SAPD/
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Conclusions
• Funding for mission-oriented, biologically-based antimicrobial/antitoxin R & D is needed
• Explore synergistic effects using mixed agent defeat components
• Work with subject matter experts to develop and optimize CONOPS
• Bring back specimens