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Published on : Mar 14, 2014
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Slide 1 - Biologic Antimicrobial Countermeasures “The enemy of my enemy is my friend*” Devon Byrd DTRA/ASX * usual caveats apply…
Slide 2 - 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
Slide 3 - DECON Direct Action Biologic Countermeasures Cut Across Agent Defeat Missions DISRUPT DEFEAT DESTROY
Slide 4 - Bacteriophage (or phage for short)kill bacteria
Slide 5 - Generic Bacteriophage Structure
Slide 6 - Lytic Phage Replication
Slide 7 - Lysis of bacterial cells by phage (courtesy of Ry Young, TAMU)
Slide 8 - As lytic phage propagate, bacteria are destroyed
Slide 9 - 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
Slide 10 - 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
Slide 11 - 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
Slide 12 - 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
Slide 13 - Interaction of MccJ25 with RNAP secondary channel: a cork in the bottle
Slide 14 - Non-bacterial Sources Cecropins Thanatin Androctonin Defensins Magainins Bombinins Citropins Arthropods Amphibians Fish Pardaxin Parasin Hepcidin Nematodes ASABF (Ascaris suum antibacterial factor)
Slide 15 - Locations GSL Amazon Crimea Azov Sea Rift Valley Baikal Region
Slide 16 - 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
Slide 17 - Potency of selected AMPs *NOTE: values are extrapolated from reported data
Slide 18 - 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
Slide 19 - 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/
Slide 20 - 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