Phage Therapies and other Bacteriolytic Approaches

The idea of using bacteriophages as weapons to combat infectious diseases is older than the application of low-molecular-weight antibiotics. In fact, there are a large number of mainly anecdotal reports of the successful use of bacteriophages especially in Eastern Europe and under military conditions [61]. With the advent of the modern antibiotic area, the interest in that approach faded, and, thus, we do not now have access to clinically valid, controlled data that meet today's standards. The increasing threat of rising antibiotic resistance has led to a renewed interest in phage therapy itself as well as in therapeutic approaches derived from the knowledge of modern phage biology.

In principle, the concept appears appealing, because phages can be viewed as a self-adapting therapy in that phages could replicate as long as target bacteria are present and would stop doing so if the infection is cured. However, several problems remain so far unresolved, such as the high selectivity of a phage for a single species or even single strains, the high rate of resistance mutations (about three magnitudes higher than conventional antibiotics), and concerns about safety and immunogenicity as well as cost, to mention just a few. A lively discussion about the pros and cons together with conflicting statements about the chances of resolving these open questions can be found in two recent detailed statements published in Nature Biotechnology in 2004 [88, 89]. So long as further experimental data are lacking, especially animal model results and eventually clinical trials, the concept must be regarded as speculative.

Inspired by the phage concept, other groups have tried to use phage products involved in the killing of bacteria or even bacteriolytic enzymes not derived from phages as therapeutics per se, thereby avoiding the complexity of a whole phage therapeutic strategy. For example, lytic enzymes encoded by bacteriophages have been used to kill bacteria with excellent efficacy [90], and other bacteriolytic enzymes of different origin have also been investigated. One of the furthest progressed projects is provided by lysostaphin, an enzyme capable of hydrolyzing the interpeptide bridge of staphylococcal cell walls and thus leading to rapid lysis of the pathogen. A special formulation of this enzyme is presently undergoing clinical phase I/II trials for the nasal eradication of S. aureus by Biosynexus [91], and the enzyme has also shown some promising efficacy in staphylococcal biofilm eradication as well as in an endocarditis model, one of the most challenging animal infection models [92]. However, some questions remain to be solved before systemic application can be envisaged, which in the same way as for phage therapy itself are linked to safety and immunogenicity, narrow spectrum range, and resistance development.

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