Abstract
The therapeutic potential of phages has been considered since their first identification more than a century ago. The evident concept of using a natural predator to treat bacterial infections has, however, since then been challenged considerably. Initially, the vast success of antibiotics almost eliminated the study of phages for therapy. Upon the renaissance of phage therapy research, the most provocative and unique properties of phages such as high specificity, self-replication and co-evolution prohibited a rapid preclinical and clinical development. On the one hand, the typical trajectory followed by small molecule antibiotics could not be simply translated into the preclinical analysis of phages, exemplified by the need for complex broad spectrum or personalized phage cocktails of high purity and the more complex pharmacokinetics. On the other hand, there was no fitting regulatory framework to deal with flexible and sustainable phage therapy approaches, including the setup and approval of adequate clinical trials. While significant advances are incrementally made to eliminate these hurdles, phage-inspired antibacterials have progressed in the slipstream of phage therapy, benefiting from the lack of hurdles that are typically associated with phage therapy. Most advanced are phage lytic enzymes that kill bacteria through peptidoglycan degradation and osmotic lysis. Both phages and their lytic enzymes are now widely considered as safe and have now progressed to clinical phase II to show clinical efficacy as pharmaceutical. Yet, more initiatives are needed to fill the clinical pipeline to beat the typical attrition rates of clinical evaluation and to come to a true evaluation of phages and phage lytic enzymes in the clinic.
Highlights
Laboratory of Gene Technology, Department of Biosystems, KU Leuven, Kasteelpark Arenberg 21, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Menoufia University, Shebin ElKoum 51132, Egypt
Isolated phages equipped with putative depolymerases or their isolated depolymerases successfully rescued mice and Galleria mellonella larvae infected by a hypervirulent K. pneumoniae strain, which is a hyper-producer of capsular polysaccharide [3,4,5,6,7]
No adverse events were attributed to phages targeting P. aeruginosa, S. aureus and E. coli
Summary
Bacteriophages have inspired to be used as antibacterial therapeutics. The first phage-borne depolymerases are evaluated preclinically, while phage-inspired antibiotics based on phage-host interactions are in the discovery phase with a single small molecule hit selected. Both phages and lytic enzymes have been demonstrated to be efficient and safe in extensive preclinical studies [21,22,23,24,25]. The authors underlined the need for more clinical studies on a higher number of different phage lytic enzymes and phages to ensure an effective translation into novel, safe and approved antibacterial products, especially given the typically high attrition rates during clinical analysis and the currently limited number of ongoing clinical trials. While none of them have reached clinical implementation as pharmaceuticals yet, we explain why phage lytic enzymes moved significantly faster through the development pipeline, and why unique properties of phages represent, simultaneously, their high potential, but are the reason for a delayed development process
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