Carl R. Merril, Dean Scholl, and Sankar Adhya




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Therapeutic Use of Phage Products and Components


Phage gene products and components may also serve as antibacterial therapeutic agents. While such applications lose the exponential growth capacity of phage they may still be highly effective. For example, it has been suggested that phage-encoded polypeptides could be developed into a new class of antibiotics (9). This suggestion is based on the recognition that the small-genome phages X174 and Qencode polypeptides that interfere with bacterial wall biosynthesis and that such inhibition can results in bacterial lysis. In another use of phage gene products it has been demonstrated that phage encoded endolysins that disrupt the peptidoglycan matrix of the bacterial cell wall and holins that permeabilize bacterial membranes can also serve as effective antibacterial agents. A single dose of a phage lysin, specific for streptococci groups A, C and E was capable of clearing these bacteria both in vitro and in vivo in mouse upper respiratory infections (54). As this lysin has little if any affect on other commensal organisms it should be less disruptive of the oral and upper respiratory ecology than most antibiotic treatments. A similar result was obtained when a phage (the g phage of Bacillus anthracis) encoded enzyme, PlyG lysine was used to rescue mice infected with Bacillus cereu, a bacterial strain that is closely related to Bacillus anthracis (66). No resistant B. cereu strains were detected following such treatment. In addition, as ATP released when PlyG lysine destroys B. anthracis, this enzyme in conjunction with luciferin/luciferase can also be used to rapidly detect γ-sensitive bacilli and their germinating spores. In this application spores are detected by first immobilizing them on filter membranes. They are then incubated with germinant and treated with PlyG lysine and luciferin/luciferase. Emitted light is detected using a hand-held luminometer. This system was able to detect as few as 100 spores (66).

Phage encoded lysin enzymes have also been used prophylacticly. Gaeng et al. developed a bacterial strain that secretes the functional bacteriophage lysin enzymes Ply511 and Ply118. They used this bacterial strain to eliminate Listeria monocytogenes from dairy starter cultures (used in the production of cheese) (29).


Concluding Remarks


While phage therapy has been employed continually since the initial discoveries of these viruses at the beginning of the 20th century these clinical applications have never faced the scrutiny now required in countries that that require certification of pharmacological agents. Such certification is based on the results of studies of efficacy and pharmacokinetic in animals and humans. As discussed, there are a number of historical reasons for this deficiency including the overshadowing discovery of the antibiotics with their broader antibacterial host range. However, phage deserve careful review as they may provide ideal therapeutic agents for the treatment of emerging antibiotic resistant bacterial strains and as Lederburg suggested for the treatment of epidemics, such as cholera in refugee camps (42). They may prove especially useful in agricultural applications where their high specificity can be used to treat a bacterial infection without disturbing the larger ecological systems as is often the problem with broad bacterial host range antibiotics (42). These suggestions are strengthen by the recent observations that many antibiotic resistant bacterial strains are arising through clonal selection. In recognition of this growing problem the FDA recently announced that it is re-evaluating livestock antibiotics currently on the market. In this regard, the FDA is now requiring manufacturers of proposed livestock pharmaceuticals to determine whether newly proposed antibiotics will be associated with the emergence of pathogenic organisms with resistance to drugs currently in use for the treatment of human diseases (37).

The lack of genetic variability in antibiotic resistant bacteria suggests that the resulting pathogenic bacteria may offer ideal targets for phage therapy. Klugman reported that only 10 strains of pneumococcus are associated with 75% of the cases of antibiotic resistant childhood pneumonia and one half of these cases are caused by a single strain “Spain 23-E”. Similar results were found by Herminia de Lencastre in a study of methicillin resistant staphylococcus aureus. In this study only 5 strains of methicillin resistant staphylococcus aureus were found in 70% of 3,000 clinical isolates from 14 countries (38).


In addition to the potential of phage for the treatment of antibiotic resistant bacterial infections, phage with their generally narrow host range may be better suited than the currently employed antibiotics for a number of clinical applications. For example, in the treatment of bacterial infections, phage with their narrow host range can be targeted toward the specific pathogen without disturbing complex bacterial ecological systems such as those associated with the human gastrointestinal system. Applications of phage to treat infections may eliminate the iatrogenic effects of antibiotics such as the antibiotic related diarrhea diseases that range from “nuisance diarrhea to colitis associated with Clostridium difficile infections (8).

Despite the clear need and in some cases advantages, there may be some concern over the view of regulatory agencies concerning approval of phage as an antibiotic therapy. However, these agencies are acutely aware of the problems associated with antibiotic resistant organisms and the need for new approaches to this problem. As for the safety of phage therapy we are normally in contact with phage throughout our life-time, with the complex interactions of bacteria and these viruses in our colon, upper respiratory system and on our skin. In this regard, many of the phages in current collections were isolated from human waste. While some phage carry harmful genes, it should be possible to eliminate these phage or those genes from our collections of therapeutic phage. In addition, it should be noted that Hans Ochs and his colleagues have been using phage as a means to determine the extent of immune deficiencies and as a probe of the immune system in human studies for the past 3 decades (56, 57). One additional fact that may be of interest is that many vaccines for human consumption were found, in the 1970s, to be contaminated with phage (from contaminated fetal calf serum used to produce these vaccines). Despite this contamination an Executive order was issued to permit their continued use (48, 49).

Development of therapeutic phage will require a commitment to fulfill the scientific requirements required of current pharmaceutical agents. In this effort the years of experience gained from the use of phage to discover many of the basic tenets of molecular biology should prove to be an asset. This information in addition to the encouraging results of recent controlled animal experiments, demonstrating the capacity of phage to rescue animals with life threatening infections, suggest that such an effort may result in the development of needed antibacterial therapeutic agents.


References


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Bacteria

Phage

Gene

Gene Product/PhenotypeEscherichia coli

O157:H7933,H-19B

ФFC3208

λ

λstx

hly2

lom

borShiga toxins

Enterohemolysin

Serum resistance

Host cell envelope proteinShigella flexneriSfi6

sfll,sfV,sfXoac

gtrllO-antegen acetylase

Glucosyl transferaseSalmonella entericaSopEФ

Gifsy-2

Gifsy-2

Gifsy-1

ε34sopE

sodC-1

nanH

gipA

rfbType III effector

Superoxide dismutase

Neuraminidase

Insertion element

GlucosylationVibrio choleraCTXΦ

K139

VPIΦctxAB

glo

tcpCholera toxin

G-protein like

TCP pilinPseudomonas aeruginosaΦCTXctxCytotoxinClostridium botulinumC1C1NeurotoxinStaphylococcus aureusNA

Φ13

TSST-1see,sel

entA,sak

tstEnterotoxin

EnterotoxinA,staphylokinase

Toxic shock syndrom-1Streptococcus pyogenesT12speAErythrogenic toxinCorynebacterium diptheriaeβ-phagetoxDiptheria toxin

Table 48-1. A list of Phages that carry toxin genes (adapted from reference 11)

Figure 48-1. Diagram of tail protein genome encoding regions for the coliphages K1, K5, K1-5 and the Salmonella phage SP6. All of these phages share a similar promoter region and an intergenic region with a putative transcription terminator. This “modular” genomic construct suggests that a horizontal gene transfer mechanism for host range variation in nature that can be adapted for phage to be used as therapeutic antibacterial agents. In addition, these phages display additional qualities necessary for phages that will be used in antibacterial therapy; they produce progeny phage with a large burst size, and also show little if any loss of titer on storage.

Figure 48-2. The distribution of phage pfu’s in mice following various routes of administration. This graph was adapted from data from a 1973 experiment in which germ free mice were inoculated with a single dose of 2X1012 pfu Lambda phage. In these experiments oral administration of phage resulted in the detection of a systemic level of phage tissue titers that were 7 to 8 orders of magnitude lower than that achieved by systemic administration of phage (30).

Figure 48-3 Graphic representation of data from the 1943 infectious disease model in which mice were inoculated by intracerebral injection of the bacteria Shigella dysenteriae (at an LD50 level) were compared with uninfected control mice. All of the mice in this experiment were injected with 109 pfu of phage i.p. which was administered at the same time as the bacterial inoculation. The bacteriophage level in the blood of the uninfected animals was compatible with the dilution of the phage concentration in the total fluid volume of the mouse and the lower levels in the brain reflect the relatively smaller blood content in the brain. However, in the infected animals the phage particles are observed to increase at the site of the infection, the brain while the blood levels of phage appear to be a “reflection of the events occurring in the brain” (22).


Figure 48-4 is a graphical representation of data presented by Smith and Huggins (67). In this set of experiments all of the animals received an intracerebral inoculation of 5X102cfu of an E. coli K1. The animals treated with phage were injected with 3X108 pfu of phage intramuscularly (into the gastrocnemius muscle) at the same time as the bacterial inoculation. These graphs were derived from the data published in tables 9 and 10 in their paper


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