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Inquiry - Alanine

Vincent Wu

on 25 November 2012

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Transcript of Anthrax

Bacillus Anthracis is initially in spore form    -> Nose/mouth    -> Bronchioles (lungs)    -> Alveoli    -> Alveolar macrophage    -> Lymph nodes         GERMINATION    -> Bloodstream Anthrax Lethal Factor

By: Alanine Pathway of Spores in the Body YYEIGKILSR DILSKINQPY QKFLDVLNTI KNASDSDGQD Outline So How Do You Die? - Apoptosis of endothelial cells

- Shock-induced death Protective Antigen and Lethal Factor Protective Antigen and Lethal Factor Lethal Factor Structure Lethal Factor Active Site Domain 4: Metalloprotease Background
Bacterial Transmission Pathway
Anthrax Toxin Invasion
Lethal Factor Mode of Action
Treatment BACKGROUND Bacillus
Anthracis Domains II, III, and IV form a 40 AA groove that binds the 16 AA N-terminal of MAPKK

Groove has a general negative potential

16 AA N-terminal of MAPKK has 3 lysines involved in docking site for MAPK

 LF is very selective for MAPKK Lethal Factor Target - MAPKK Treatment Antibiotics
Developing Treatments Proposed Treatment Raxibacumab Monoclonal antibody inhibiting the action of protective antigen (14) (11-13) (14) (15) Lethal Factor Edema Factor Protective
Antigen (18-21) (6) (2-5) (16) (17) (8) (9) References (1)BLAST: Basic Local Alignment Search Tool [Internet]. 2011 [cited 2011 Sept 30]. Available from: http://blast.ncbi.nlm.nih.gov/Blast.cgi. (2)Agrawal A, Pulendran B. Anthrax lethal toxin: a weapon of multisystem destruction. Cell Mol Life Sci. 2006;61(22):2859-2865. doi: 10.1007/s00018-004-4251-4
(3)Watson L, Kuo S, Katki K, Dang T, Park S, Dostal D, Tang W, Leppla S. Anthrax toxins induce shock in rats by depressed cardiac ventricular functions. PLoS ONE. 2007;2(5):466. doi: 10.1371/journal.pone.0000466
(4)Karwa M, Loganathan RS, Kvetan V. Principles of Critical Care. The McGraw-Hill Compaines; 2005. Chapter 61, Biowarfare Agents.[cited 2011 Oct 1]. Available from: http://www.accessmedicine.com/content.aspx?aID=2292424.
(5)Schwartz BS. CURRENT Medical Diagnosis & Treatment. The McGraw-Hill Companies; 2012. Chapter 33, Bacterial & Chlamydial Infections. [cited 2011 Oct 1]. Available from: http://www.accessmedicine.com/content.aspx?aID=17820
(6)Grey MR, Spaeth KR. The Bioterrorism Sourcebook. The McGraw-Hill Companies; 2006. Chapter 14, Anthrax. Available from: http://www.accessmedicine.com/content.aspx?aID=2740833
(7)Kirby JE. Anthrax lethal toxin induces human endothelial cell apoptosis. Infect Immun. 2004;72(1):430-439.
(8)Shen Y, Zhukovskaya NL, Guo Q, Floria J, Tang W. Calcium-independentcalmodulin binding and two-metal–ion catalytic mechanism of anthrax edemafactor. EMBO Journal. 2005;24(5):929-941.
(9)Petosa C, Collier RJ, Klimpel KR, Leppla SH, Liddington RC. Crystal structure ofanthrax toxin protective antigen. Nature. 1997;385:833-838.
(10)RCSB Protein Data Bank – 1JKY Structure Summary [Internet]. 2001. Adapted from: The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC.
(11)SciAna FilmWorks. Anthrax Toxin Delivery [Video on the Internet]. [Updated 2009 Feb 5; cited 2011 Nov 15]. Available from: http://www.youtube.com/watch?v=44T9PuvKkf0
(12)Verma K, Gu J, Werner E. Tumor endothelial marker 8 amplifies canonical Wnt signaling in blood vessels. PLoS ONE. 2011;6:1-9. (13)Cunningham K, Lacy DB, Mogridge J, Collier RJ. Mapping the lethal factor and edema factor binding sites on oligomeric anthrax protective antigen. Proc Natl Acad Sci U S A. 2002;99(10):7049-53. doi:10.1073/pnas.062160399.
(14)Pannifer AD, Wong TY, Schwarzenbacher R, Renatus M, Petosa C, Bienkowska J, Lacy DB, Collier RJ, Park S, Leppla SH, Hanna P, Liddington RC. Crystal structure of the anthrax lethal factor. [Internet]. Nature. 2001 Nov 8 [cited 2011 Oct 1];414(6860):229-33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11700563
(15)Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol. 1999;15(1), 269–290. doi: 10.1146/annurev.cellbio.15.1.269
(16)The anthrax vaccine boondoggle [Internet]. 2011 [cited 2011 Nov 9]. Available from: http://www.forbes.com/sites/stevensalzberg/2011/10/30/the-anthrax-vaccine-boondoggle/
(17)Animation Illustrating the Role of Tetracyclines in Blocking Translationduring Bacterial Protein Synthesis [Internet]. 2004 [cited 2011 Nov 9]. Available from: http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit2/control/tetres.html
(18)Migone T-S, Subramanian GM, Zhong J, Healey LM, Corey A, Devalaraja M, Lo L, Ullrich S, Zimmerman J, Chen A, Lewis M, Meister G, Gillum K, Sanford D, Mott J, Bolmer SD. Raxibacumab for the treatment of inhalational anthrax. N Engl J Med. 2009 Jul 9;361(2):135-44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19587338
(19)Mazumdar S. Raxibacumab. mAbs [Internet]. 2009;1(6):531-8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2791309&tool=pmcentrez&rendertype=abstract
(20)Evaluation KP. Key Paper Evaluation Raxibacumab for inhalational anthrax: an effective specific therapeutic approach? Expert Opin Investig Drugs. 2010;909-911.
(21)Raxibacumab [Internet]. 2011 [cited 2011 Nov 9]. Available from: http://www.hgsi.com/raxibacumab-2.html (1) (7) (10) (13) (14) Advantages Specific to Protective Antigen
Combination with Antibiotics
Pre- and Post-Exposure
Long Therapeutic Window
More Effective than Antibiotics Disadvantages Side Effects
Intravenous is Inconvenient
Interactions with Other Diseases (18-21)
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