Abstract
Phage-derived therapies comprise phage therapy and the use of phage-derived proteins as anti-bacterial therapy. Bacteriophages are natural viruses that target specific bacteria. They were proposed to be used to treat bacterial infections in the 1920s, before the discovery and widespread over-commercialized use of antibiotics. Phage therapy was totally abandoned in Western countries, whereas it is still used in Poland, Georgia and Russia. We review here the history of phage therapy by focusing on bone and joint infection, and on the development of phage therapy in France in this indication. We discuss the rationale of its use in bacterial infection and show the feasibility of phage therapy in the 2020s, based on several patients with complex bone and joint infection who recently received phages as compassionate therapy. Although the status of phage therapy remains to be clarified by health care authorities, obtaining pharmaceutical-grade therapeutic phages (i.e., following good manufacturing practice guidelines or being “GMP-like”) targeting bacterial species of concern is essential. Moreover, multidisciplinary clinical expertise has to determine what could be the relevant indications to perform clinical trials. Finally “phage therapy 2.0” has to integrate the following steps: (i) follow the status of phage therapy, that is not settled and defined; (ii) develop in each country a close relationship with the national health care authority; (iii) develop industrial–academic partnerships; (iv) create academic reference centers; (v) identify relevant clinical indications; (vi) use GMP/GMP-like phages with guaranteed quality bioproduction; (vii) start as salvage therapy; (vii) combine with antibiotics and adequate surgery; and (viii) perform clinical trials, to finally (ix) demonstrate in which clinical settings phage therapy provides benefit. Phage-derived proteins such as peptidoglycan hydrolases, polysaccharide depolymerases or lysins are enzymes that also have anti-biofilm activity. In contrast to phages, their development has to follow the classical process of medicinal products. Phage therapy and phage-derived products also have a huge potential to treat biofilm-associated bacterial diseases, and this is of crucial importance in the worldwide spread of antimicrobial resistance.
Highlights
Each bacteriophage is mostly specific to bacterial species or even specific to a strain, which means as a therapeutic agent they have no deleterious effect on microbiomes, a fact that is in huge contrast with the use of antibiotics, even narrow spectrum molecules [5]
Pherecydes Pharma and the Lyon Hospitals Board (Hospices Civils de Lyon) selected phages targeting S. aureus and active on most strains implicated in bone and joint infection, with the possibility of GMP production for use in clinical trials and/or with a temporary authorization for use
Prosthetic joint infection seems to be a relevant indication for phage therapy, especially in patients for whom prosthesis explantation might be associated with significant loss of function
Summary
Bacteriophages (phages for short) are viruses that target bacteria [1,2]. Phage diversity is remarkable at the nucleotide sequence level, but more than 95% of described species belong to the Myoviridae, Podoviridae and Siphoviridae families, with conservative structural proteins that form viral particles [3]. Lytic phages hijack the cell machinery to produce hundreds of new virions, with lysis of the bacterial host by production of different proteins such as a lysin ( called endolysin) that has enzymatic activity and disrupts the bacterial cell wall, allowing the release of progeny virions from the lysed cell. This can give rise to an exponential selfmaintaining phenomenon, with the virions replicating until there is nothing left of the host (Figure 1) [1,2,4].
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