The resurgence of research into phage biology and therapy is, in part, due to the increasing need for novel agents to treat multidrug-resistant infections. Despite a long clinical history in Eastern Europe and initial success within the food industry, commercialized phage products have yet to enter other sectors. This relative lack of success is, in part, due to the inherent biological limitations of whole phages. These include (but are not limited to) reaching target sites at sufficiently high concentrations to establish an infection which produces enough progeny phages to reduce the bacterial population in a clinically meaningful manner and the limited host range of some phages. Conversely, parallels can be drawn between antimicrobial enzymes derived from phages and conventional antibiotics. In the current article the biological limitations of whole phage-based therapeutics and their derived antimicrobial enzymes will be discussed. In addition, the ability of more complex formulations to address these issues, in the context of medical and non-medical applications, will also be included.
Enterotoxigenic Escherichia coli (ETEC) strains are an important cause of bacterial diarrheal illness in humans and animals. Infections arising from ETEC could potentially be treated through the use of bacteriophage (phage) therapy, as phages encode for enzymes capable of bacterial cell lysis. vB_EcoP_SU7 was isolated from the Käppala wastewater treatment plant in Stockholm, Sweden, and propagated on an ETEC strain exhibiting the O:139 serovar. Transmission electron microscopy confirmed that vB_EcoP_SU7 belongs to the Podoviridae family and has the rare C3 morphotype of an elongated head. Bioinformatic analyses showed that the genome was 76,626 base pairs long and contained 35 genes with predicted functions. A total of 81 open reading frames encoding proteins with hypothetical function and two encoding proteins of no significant similarity were also found. A putative tRNA gene, which may aid in vB_EcoP_SU7’s translation, was also identified. Phylogenetic analyses showed that compared to other Podoviridae, vB_EcoP_SU7 is a rare Kuravirus and is closely related to E. coli phages with the uncommon C3 morphotype, such as ECBP2, EK010, vB_EcoP_EcoN5, and vB_EcoP_SU10. Phage vB_EcoP_SU7 has a narrow host range, infecting 11 out of the 137 E. coli strains tested, a latency period of 30 min, a burst size of 12 PFU/cell, and an adsorption rate of 8.78 × 10−9 mL/min five minutes post infection. With a limited host range and poor infection kinetics, it is unlikely that SU7 can be a standalone phage used for therapeutic purposes; rather, it must be used in combination with other phages for broad-spectrum therapeutic success.
In this study, we looked at the population dynamics of a two phages-one host system using phages vB_EcoP_SU10 (SU10) and vB_EcoD_SU57 (SU57) and the bacteria Escherichia coli, strain ECOR57. Phage-specific growth curves were observed where infections by SU10 resulted in a moderate production of phages and infections by SU57 resulted in a fast and extensive production of phage progeny. Sequentially adding SU10 followed by SU57 did not produce a significant change in growth rates, whereas adding SU57 followed by SU10 resulted in a decrease in SU10 titer The efficiency of the plating assays showed that ECOR57 exhibited a resistance spectrum after infection by both the single and combined phages. Phage-resistant bacteria exhibited four different morphotypes (i.e., normal, slimy, edgy, and pointy). The normal and edgy morphotypes had a high frequency of developing resistance. Bacterial growth and biofilm assays indicated that the edgy and pointy morphotypes reached a stationary phase faster and produced more biofilm compared to the wild type. These findings suggest that the dynamic structure of phage–bacteria communities dictate resistance evolution and development. Understanding when and how resistances arise and phage(s)–hosts interactions could aid in the design of phage therapy treatments.
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