Therapeutic and Prophylactic Applications of Bacteriophage Components in Modern Medicine

Next Section Abstract As the interactions of phage with mammalian innate and adaptive immune systems are better delineated and with our ability to recognize and eliminate toxins and other potentially harmful phage gene products, the potential of phage therapies is now being realized. Early efforts to use phage therapeutically were hampered by inadequate phage purification and limited knowledge of phage–bacterial and phage–human relations. However, although use of phage as an antibacterial therapy in countries that require controlled clinical studies has been hampered by the high costs of patient trials, their use as vaccines and the use of phage components such as lysolytic enzymes or lysozymes has progressed to the point of commercial applications. Recent studies concerning the intimate associations between mammalian hosts and bacterial and phage microbiomes should hasten this progress.

The human superorganism is made up of eukaryotic and prokaryotic cells, in which the prokaryotic cells far outnumber the eukaryotic cells. Given our current limited understanding of ourselves as super organisms it is remarkable that we have achieved successes, albeit limited, in developing therapies for infectious diseases. This was especially true in the 19th and 20th centuries when specific strains of bacteria were first being discovered and in some cases associated with animal or human disease states.

The therapeutic advances realized at that time were based on limited observations and heroic empirical efforts, such as the discovery of the antisyphilitic compound Salvarsan or 606 (in reference to the hundreds of compounds screened) by S. Hata in Paul Ehrlich’s laboratory in the early 1900s (Sneade 2005).

Given the state of knowledge at the beginning of the 20th century concerning microbiology and the immune defense mechanisms, the discovery of bacteriophage (phage) viruses that kill specific strains of bacteria was welcomed. However, soon after their discovery a number of issues arose, including a controversy as to whether the bacteriophages were self-replicating particles or a lytic enzymatic activity activated in the bacteria. One of the pioneers associated with their discovery, Félix d’Herelle, consulted with Albert Einstein who reassured d’Herelle that his experiments designed to prove that they were self-replicating particles were valid (Summers 1999). Perhaps more serious were the problems that arose owing to a lack of appreciation of the narrow host range of most phage strains, so that a phage isolated from an infected patient did not appear to be effective in treating another patient with a seemingly similar infection. In addition, there was a lack of knowledge of bacterial toxins and methods to purify phage preparations so that they were not contaminated with such toxins. These problems coupled with inadequately designed animal and clinical experiments were some of the factors that led, in the United States, to the development of a government agency to oversee therapeutic developments and claims (Merril et al. 2003, 2006).

In addition to these early problems, the discovery of the broad host range antibiotics—beginning with penicillin—more than 85 years ago, resulted in the virtual abandonment of efforts to continue in the development of the phage as a therapeutic antibacterial agent in the United States. However, the increasing incidence of antibiotic-resistant bacterial strains, particularly the bacterial strains commonly found in hospital settings, has prompted a reexamination of the potentials of phage antibacterial therapies. In addition, there is now an increased awareness of clinical problems associated with the extended bacterial host range of most commonly used antibiotics. Although an extended bacterial host range was one of the criteria used in searching for clinically relevant antibiotics, as this property partially alleviated the need to accurately identify infecting bacterial species before therapy was initiated, it is now recognized that such extended host range antibiotics often result in collateral damage to the natural human microbiome (Jernberg et al. 2010). Even before the medical community recognized the extent of this problem, it was clear that individuals treated successfully for one species of infectious agent would often succumb to an infection by another secondary foreign bacterial strain.

As most phage strains have a narrow bacterial host range, they are expected to cause minimal perturbations of the normal human microbiome when they are used to treat bacterial infections. Also, as their mechanisms of antibacterial activity of phage are not related to the mode of action of the antibiotic therapies, it should be possible to find effective phage therapies for the antibiotic-resistant disease-associated bacterial strains.

In addition our ability to develop molecular tools that permit manipulations of phage genomes and our knowledge of the microbiology and physiology of phage along with some knowledge of their interactions with the human immune system, they are beginning to be adapted to serve as vaccines. The phage strains are also being used to produce antibacterial proteins that are encoded in their genomes. By manipulating the promoters for these genes, it is possible to produce antibacterial proteins such as the phage-based lysozymes in quantity. The clinical applications of phage, including the development of phage-based vaccines and phage products are now beginning to enter commercial development.