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Vol. 93, Issue 8, 3188-3192, April 16, 1996 (phage / bacteria / reticuloendothelial
system / toxins / antibiotic resistance)
* Laboratory of Biochemical Genetics, National Institute of Mental
Health Neuroscience Center at Saint Elizabeths, Washington, DC 20032;
Contributed by Sankar Adhya, December 21, 1995
The increased prevalence of multidrug-resistant bacterial pathogens
motivated us to attempt to enhance the therapeutic efficacy of
bacteriophages. The therapeutic application of phages as antibacterial agents was impeded by several factors: (i) the failure to
recognize the relatively narrow host range of phages; (ii)
the presence of toxins in crude phage lysates; and (iii) a
lack of appreciation for the capacity of mammalian host defense
systems, particularly the organs of the reticuloendothelial system, 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 Escherichia coli phage
0027-8424/96/933188-5/0
Microbiology
Long-circulating bacteriophage as antibacterial agents
,,,
Exponential Biotherapies, Inc., 19 West 34th Street, Penthouse,
New York, NY 10001; and Laboratory of Molecular Biology,
National Cancer Institute, National Institutes of Health,
Bethesda, MD 20892
and of Salmonella
typhimurium phage P22. We demonstrated that the long-circulating
mutants also have greater capability as antibacterial agents than
the corresponding parental strain in animals infected with lethal doses
of bacteria. Comparison of the parental and mutant capsid proteins
revealed that the relevant mutation altered the major phage head
protein E. 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.
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