Bacteriophage Therapy

BACTERIOPHAGE THERAPY       

Bacteriophages (phages) are viruses which specifically infect and kill bacteria, but they are unable to attack mammalian cells. In fact, their specificity is even more profound, in that a particular bacteriophage will only infect a given species of bacterium and often is even strain-specific. There are an estimated 10³¹ bacteriophages on the planet, and viral predation accounts for a significant part of carbon recycling in the oceans. These viruses have existed on earth in conjunction with bacteria for nearly 4 billion years and so are just as adept as their prey at changing with their environment.

The structure of a typical bacteriophage is shown in Figure 27.2. The genome is normally double-stranded DNA and this is enclosed within a protein capsid. At the tips of the tail fibres are receptors which recognize attachment sites on the bacterial cell surface. When the phage encounters a host bacterium it attaches via the tail fibres and injects its DNA into the cell. This DNA then takes over the cell’s metabolic machinery and the cell devotes itself to the production of new virus particles (virions). When the process is complete the infected cell may contain some hundreds of progeny virions and these are liberated from the cell by the action of endolysins, which are virally encoded enzymes acting firstly on the cytoplasmic membrane and then on the peptidoglycan layer. The newly released viruses are then available to attack other host cells within the vicinity. Not all phages go through this lytic cycle. Following infection of the cell some viruses incorporate their DNA within the host cell DNA where it remains as a prophage; usually it causes no harm and each time the bacterial cell subsequently divides the viral DNA divides also. These are known as temperate bacteriophages and they induce in their host a state of lysogeny. This phenomenon can be responsible for conferring on the host cell additional virulence characteristics such as toxin production or resistance. At some later point in time the prophage may break free and embark on a lytic infection cycle similar to that described above.

Bacteriophages were first discovered at the beginning of the 20th century and it was quickly realized that they might have a use in the therapy of bacterial infections in humans. In the early days very little was known about phage biology, particularly their specificity and the presence of temperate phages. Despite this there was considerable success in treating gastrointestinal infections such as dysentery and cholera, wound infections and urinary tract infections. This situation was short-lived, however, and as the number of workers in the field increased so the success rate decreased and toxicity issues primarily due to endotoxin release increased. With the emergence of antibiotics in the 1940s the use of phage as a therapy declined to virtually zero except in the former Soviet Union and parts of eastern Europe.

In the intervening period bacteriophages have been studied extensively, not as a means of treating infections but for their role in the molecular biology revolution. As a consequence, we now know a great deal about these viruses and are well placed to revisit their use in therapy. In addition, the former Soviet Union has continued to use phages to treat infections over the past 70 years and so has a vast amount of clinical knowledge available. Given the improved relationship between East and West since the breakdown of the Berlin Wall there is now a greater spirit of cooperation which could be harnessed to our benefit.

Bacteriophages offer a number of therapeutic advantages over the use of antibiotics:

•                                                                        They are specific in their action, usually attacking only single species of bacteria. This has the advantage that only the infecting pathogen will be eliminated and the host microflora will remain intact. In order to broaden the spectrum of activity it is possible to use mixtures or cocktails of phages of different specificity.

•                                                                        The mode of action of phages is such that antibioticresistant strains are just as susceptible as sensitive strains.

•                                                                        The pharmacokinetic properties are unique in that after administration the number of phage particles will increase as the virus propagates and hence multiple dosing may be unnecessary.

•                                                                        The phage can be formulated for administration into a wide range of pharmaceutical products and can be administered orally, topically, and even by injection.

•                                                                        Very few incidences of side effects or allergic reactions have been reported.

•                                                                        If resistance occurs then a range of other phages may be available for use, or, if not, it is a relatively simple exercise to obtain more virulent phages from environmental sources.

•                                                                        Because phage therapy is a platform technology, the cost of bringing new phages to the clinic should not be expensive and the timescales should be short. The technology also lends itself for use in developing countries that do not have access to high-cost health care.

Care has to be taken in the selection of phages for therapy to ensure that they do not contain any toxin or virulence genes nor induce lysogeny.

There are hundreds of papers in the scientific literature describing the beneficial clinical effects of bacteriophages for the treatment of a wide range of bacterial infections. However, most of these emanate from the Soviet Union and are generally regarded to be of very poor quality. This situation needs to be addressed. Interest in phage therapy has increased dramatically in the West over the last 20 years and a number of companies are being formed in order to exploit the technology in the future. The regulatory authorities (including the Food and Drug Administration in the USA) have given approval for the use of bacteriophages in ready-to-eat food and a mixture of phages for the protection of cheeses from contamination by Listeria monocytogenes has been given GRAS (Generally Regarded As Safe) approval. Some companies have begun human clinical trials for the phage treatment of Ps. aeruginosa ear infections and for the eradication of MRSA from the nasal cavity. There are good indications that phages may play a greater role in the treatment of bacterial infections in the future.