LONG-CIRCULATING BACTERIOPHAGE AS ANTIBACTERIAL AGENTS

The increased prevalence of multidrug-resistant bacterial pathogens mo tivated us to attempt to enhance the therapeutic efficacy of bacteriop hages. The therapeutic application of phages as antibacterial agents w as impeded by several factors: (i) the failure to recognize the relati vely narrow host range of phages; (ii) the presence of toxins in crude phage lysates; and (iii) a lack of appreciation for the capacity of m ammalian host defense systems, particularly the organs of the reticulo endothelial system, to remove phage particles from the circulatory sys tem, In our studies involving bacteremic mice, the problem of the narr ow host range of phage was dealt with by using selected bacterial stra ins and virulent phage specific for them, Toxin levels were diminished by purifying phage preparations, To reduce phage elimination by the h ost 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 coil phage lambda and of Salmonella typhimuriu m phage P22. We demonstrated that the long-circulating lambda mutants also have greater capability as antibacterial agents than the correspo nding parental strain in animals infected with lethal doses of bacteri a, Comparison of the parental and mutant lambda capsid proteins reveal ed 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 phag e into therapeutically effective antibacterial agents.