The increased prevalence of multidrug resistant bacterial pathogens motivated us to attempt to enhance the therapeutic efficacy of bacterial viruses or bacteriophages (phages). Throughout this century the therapeutic application of phages as antibacterial agents was impeded by several factors: first, the failure to recognize the relatively narrow host range of phages; second, the presence of toxins in unpurified phage preparations; and third, a lack of appreciation for the capacity of mammalian host defense systems, particularly the organs of the reticuloendothelial system (RES), to remove phage particles from the circulatory system. In our studies involving bacteremic mice, the problem of the narrow host range of phage was dealt with by using selected bacterial strains and virulent phage specific for them. Toxin levels were diminished by purifying phage preparations. To reduce phage elimination by the host defense system, we developed a serial passage technique in mice to select for phage mutants able to remain in the circulatory system for longer periods of time. By this approach we isolated long-circulating mutants of phage for two different species of bacteria. We demonstrated that these long-circulating phage mutants also have greater capability as antibacterial agents than the corresponding parental strain in animals infected with lethal doses of bacteria. The use of toxin-free, bacteria-specific phage strains, combined with the serial passage technique, may provide insights for developing phage into therapeutically effective antibacterial agents which could significantly augment our ability to treat infectious diseases. There are a number of infectious diseases that affect the CNS directly and indirectly that may benefit from the development of such therapeutic agents. In addition, the approach taken in this effort provides a paradigm for the development of gene therapy vectors that also may be of use in the future in the treatment of diseases of the CNS that result from inborn errors of metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH002702-03
Application #
6162928
Study Section
Special Emphasis Panel (LBG)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Kyuregyan, Karen K; Poleschuk, Valentina F; Zamyatina, Natalya A et al. (2005) Acute GB virus B infection of marmosets is accompanied by mutations in the NS5A protein. Virus Res 114:154-7
Adhya, Sankar; Black, Lindsay; Friedman, David et al. (2005) 2004 ASM Conference on the New Phage Biology: the 'Phage Summit'. Mol Microbiol 55:1300-14
Scholl, Dean; Adhya, Sankar; Merril, Carl (2005) Escherichia coli K1's capsule is a barrier to bacteriophage T7. Appl Environ Microbiol 71:4872-4
Scholl, D; Kieleczawa, J; Kemp, P et al. (2004) Genomic analysis of bacteriophages SP6 and K1-5, an estranged subgroup of the T7 supergroup. J Mol Biol 335:1151-71
Merril, Carl R; Scholl, Dean; Adhya, Sankar L (2003) The prospect for bacteriophage therapy in Western medicine. Nat Rev Drug Discov 2:489-97
Scholl, Dean; Adhya, Sankar; Merril, Carl R (2002) Bacteriophage SP6 is closely related to phages K1-5, K5, and K1E but encodes a tail protein very similar to that of the distantly related P22. J Bacteriol 184:2833-6
Biswas, Biswajit; Adhya, Sankar; Washart, Paul et al. (2002) Bacteriophage therapy rescues mice bacteremic from a clinical isolate of vancomycin-resistant Enterococcus faecium. Infect Immun 70:204-10
Scholl, D; Rogers, S; Adhya, S et al. (2001) Bacteriophage K1-5 encodes two different tail fiber proteins, allowing it to infect and replicate on both K1 and K5 strains of Escherichia coli. J Virol 75:2509-15