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Phage therapy for bio-threat bacteria

Description:

TECHNOLOGY AREA(S): Chem Bio_defensebio Medical 

OBJECTIVE: Development of effective phage therapy as a medical countermeasures to treat bio-threat specific bacteria: Burkholderia mallei, Burkholderia pseudomallei, or Brucella spp. 

DESCRIPTION: The Department of Defense (DoD) has a requirement to field medical countermeasures to treat diseases resulting from intentional or environmental exposure to CBRN agents. The DoD threat agent list includes the bacteria B. anthracis, Y. pestis, F. tularensis, B. mallei, B. pseudomallei, and Brucella spp. Drug resistance to antibiotics has emerged as a major obstacle for multiple bacteria including DoD threat organisms (1). Additionally, more effective therapeutics and alternate therapies are urgently needed to cure infections caused by bio-threat bacteria including antibiotic resistant strains. The practice of phage therapy to treat bacterial infections has been conducted for almost a century (2, 3). Increased rate of antibiotic resistance in bacteria has generated interest in phage therapy. Biotechnological advances in this area allow the generation of bioengineered phages and purified phage lytic proteins (4). Suitable phage delivery systems may be required to ensure their prolonged survival, better phage retention at target site and reduction in their rapid clearance by mononuclear phagocytic system (MPS). Several nano-delivery systems composed of an assortment of different sizes, shapes, and materials have been constructed (5-9). Current research on the use of phages and their lytic proteins, specifically against multi-drug resistant bacterial infections suggests phage therapy has the potential to be used as either an alternative or a supplement to antibiotic treatment (3). The primary goal of this SBIR topic is to identify and characterize phages as an alternative to antibiotics for the treatment of diseases caused by Category B bio-threat bacteria: B. mallei, B. pseudomallei, or Brucella spp (4, 10-12).  

PHASE I: Development of phage libraries/cocktails. Key objectives of this Phase are: 1. Preparation of phage libraries/cocktails for treatment of: B. mallei, B. pseudomallei, or Brucella spp. 2. Optimize and expand phage libraries to provide therapeutic coverage of multiple, diverse strains: B. mallei, B. pseudomallei, or Brucella spp using in vitro and in situ methodologies. 3. Analyze and provide potency testing data of phages. Select phage or phage library/cocktails for in vivo testing. 

PHASE II: Determination of efficacy and toxicity data in relevant animal models. Key objectives of this Phase are: 1. Demonstrate in vivo activities of phages or phage libraries in appropriate animal models. 2. Evaluation of dose, efficacy and toxicity of phages in appropriate animal models. 3. Analyze and submit in vivo screening data. 4. As needed, Formulate, Test, and Develop enhanced delivery systems (e.g. liposomes, exosomes, phospholipid vesicles) to improve efficacy of phage candidate therapeutic cocktails in in vivo models of infection. 5. Provide a plan for Good Manufacturing Practice (GMP) manufacture of product phage or phage library/cocktails, product licensure /approval to support the Warfighter (prototypes). This plan should also support product application under an Emergency Use Authorization (EUA) or an Emergency Investigational New Drug (eIND).  

PHASE III: PHASE III: Conduct non-clinical and clinical testing of phages necessary to achieve EUA or eIND status for treatment of B. mallei, B. pseudomallei, or Brucella spp as an alternative to or in combination with current antimicrobial therapeutics 

REFERENCES: 

1: USAMRIID Medical Management of Biological Casualties Handbook. September 2014, 8th Edition.

2:  Lin DM, Koskella B, Lin HC (2017) Phage Therapy: An alternative to antibiotics in the age of multi-drug resistance. World J. Gastrointest. Pharmacol. Ther.8:162-173.

3:  Chanishvili N. (2012) Phage Therapy- history from Twort and d’Herelle through Soviet experience to current approaches. Adv. Virus Res. 83:3-40.

4:  Umaporn Yordpratum, Unchalee Tattawasart, Surasakdi Wongratanacheewin, Rasana W. Sermswan (2011) Novel lytic bacteriophages from soil that lyse Burkholderia pseudomallei, FEMS Microbiology Letters.314:81–88.

5:  S. Singla, K. Harjai, K. Raza, S. Wadhwa, O.P. Katare, S. Chhibber (2016) Phospholipid vesicles encapsulated bacteriophage: A novel approach to enhance phage biodistribution, J. of Virological Methods.236:68-76.

6:  Singla S, Harjai K, Katare OP, Chhibber S (2016) Encapsulation of Bacteriophage in Liposome Accentuates Its Entry in to Macrophage and Shields It from Neutralizing Antibodies. PloS ONE 11(4): e0153777. doi:10.1371joumal.pone.0153777.

7:  Zhigang Ju & Wei Sun (2017) Drug delivery vectors based on filamentous bacteriophages and phage-mimetic nanoparticles, Drug Delivery, 24:1898-1908.

8:  Chhibber S, Kaur J, Kaur S (2018) Liposome Entrapment of Bacteriophages Improves Wound Healing in a Diabetic Mouse MRSA Infection. Frontiers in Microbiology. 9:561.

9:  Malik DJ, Sokolov IJ, Vinner JK, Mancuso F, Cinquerrui S, Vladisavljevic GT, Clokie MRJ, Garton NJ,Stapley AGF, Kipichnikova A (2017). Formulation, stabilization and encapsulation of bacteriophage for phage therapy. Adv. Colloid Interface Sci. 249:100-133.

10:  https://www.cdc.gov/phpr/publications/2008/appendix6.pdf

11:  Fillippov AA, Sergueev KV, and Nikolich MP (2013) Bacteriophages against Biothreat Bacteria: Diagnostic, Environmental and Therapeutic Applications. J. of Bioterrorism and Biodefense. S3:010.doi:10.4172/2157-2526.S3-010.

12:  Guang-Han 0, Leang-Chung C, Vellasamy KM, Mariappan V, Li-Yen C, Vadivelu J (2016) Experimental Phage Therapy for Burkholderia pseudomallei Infection. PLoS ONE 11 (7): e0158213. doi:10.1371joumal.pone.0158213.

KEYWORDS: Bacteriophage, Phage, Biothreat, Medical Countermeasure, Biotherapeutic, Drug Screening 

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