Long-circulating bacteriophage as antibacterial agents

被引:354
作者
Merril, CR
Biswas, B
Carlton, R
Jensen, NC
Creed, GJ
Zullo, S
Adhya, S
机构
[1] EXPONENTIAL BIOTHERAPIES INC, NEW YORK, NY 10001 USA
[2] NCI, MOLEC BIOL LAB, NIH, BETHESDA, MD 20892 USA
关键词
phage; bacteria; reticuloendothelial system; toxins; antibiotic resistance;
D O I
10.1073/pnas.93.8.3188
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 lambda and of Salmonella typhimurium phage P22. We demonstrated that the long-circulating lambda 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 lambda 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.
引用
收藏
页码:3188 / 3192
页数:5
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