A guard-killer phage cocktail effectively lyses the host and inhibits the development of phage-resistant strains of Escherichia coli

Abstract

In recent years, after the emergence of a large number of multidrug-resistant bacteria, phages and phage-associated products for the prevention and control of bacterial disease have revealed prominent advantages as compared with antibiotics. However, bacteria are susceptible to becoming phage-resistant, thus severely limiting the application of phage therapy. In this study, Escherichia coli cells were incubated with lytic bacteriophages to obtain mutants that were resistant to the lytic phages. Then, bacteriophages against the phage-resistant variants were isolated and subsequently mixed with the original lytic phage to prepare a novel phage cocktail for bactericidal use. The data showed that our phage cocktail not only had notable bactericidal effects, including a widened host range and rapid lysis, but also decreased the generation and mutation frequency of phage-resistant strains in vitro. In addition, we tested our cocktail in a murine bacteremia model. The results suggested that compared with the single phage, fewer phage-resistant bacteria appeared during the treatment of phage cocktail, thus prolonging the usable time of the phage cocktail and improving its therapeutic effect in phage applications. Importantly, our preparation method of phage cocktail was proved to be generalizable. Because the bacteriophage against the phage-resistant strain is an ideal guard that promptly attacks potential phage resistance, this guard-killer dual-function phage cocktail provides a novel strategy for phage therapy that allows the natural ecology to be sustained.

Isolation and Characterization of a Novel Phage for Controlling Multidrug-Resistant Klebsiella pneumoniae

“…Due to co-evolution of the phages and their host bacteria, the construction of a phage cocktail was able to avoid bacterial phage resistance [54]. Furthermore, the construction of a phage cocktail was also able to control the multiple infections caused by different bacterial pathogens [55].…”

Applications of Personalised Phage Therapy highlighting the importance of Bacteriophage Banks against Emerging Antimicrobial Resistance

“…Nevertheless mutant generation by phase variation has also been shown to provide transient resistance to phage infection in case of Gram negative bacteria [40][41][42] . Different phages may recognise different kind of receptors including cell wall (mainly murein and teichoic acid), outer membrane proteins, flagellar components, pilli, lipopolysaccharides, capsular antigens or extracellular matrix structures to which they bind via adhesions or receptor binding proteins (RBPs) [43][44][45][46] . This provides us with a strategy to deal with the issue of bacterial mutants through designing phage cocktails wherein phages targeting different host receptors or phages against mutant strains are included.…”

Bacteriophage therapy for management of bacterial infections in veterinary practice: what was once old is new again

“…Conversely, phages have evolved great diversity and a multiplicity of attack mechanisms. It has been reported that the use of phage cocktails tends to slow the emergence of bacterial resistance as compared with the use of individual phages (Fischer et al 2013;Yu et al 2017). Phages act synergistically when used in cocktails (Schmerer et al 2014).…”