Approaches to optimize therapeutic bacteriophage and bacteriophage-derived products to combat bacterial infections

Abstract

The emerging occurrence of antibiotic-resistant bacterial pathogens leads to a recollection of bacteriophage as antimicrobial therapeutics. This article presents a short overview of the clinical phage application including their use in military medicine and discusses the genotypic and phenotypic properties of a potential "ideal" therapeutic phage. We describe current efforts to engineer phage for their improved usability in pathogen treatment. In addition, phage can be applied for pathogen detection, selective drug delivery, vaccine development, or food and surface decontamination. Instead of viable phage, (engineered) phage-derived enzymes, such as polysaccharide depolymerases or peptidoglycan-degrading enzymes, are considered as promising therapeutic candidates. Finally, we briefly summarize the use of phage for the detection and treatment of "Category A priority pathogens".

Bacteriophage-Derived Depolymerases against Bacterial Biofilm

“…In contrast, free depolymerases are genetically stable agents, active in harsh external conditions. Development of resistance to these enzymes is unlikely, which is another advantage of free proteins (obtained biotechnologically as products of recombinant genes) over the use of whole phage particles [ 99 , 111 , 112 ]. In addition, the diffusion of free enzymes seems to be more rapid and effective than that of virion-associated depolymerases [ 105 ].…”

Phage-Encoded Endolysins

“…Endolysins combined with fusion peptides (lipopolysaccharide destabilizing peptides) also promote the uptake of endolysin through the outer membrane in Gram-negative bacteria. Artilysin ® Art-175 (LYSANDO AG, Liechtenstein) is very effective against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii [ 170 ]. It is made by fusing the antimicrobial sheep myeloid peptide (29 amino acids) with endolysin KZ144 [ 79 ].…”

The Age of Phage: Friend or Foe in the New Dawn of Therapeutic and Biocontrol Applications?

“…This can help to minimize the transduction potential of the infecting bacteriophage, including the transfer of genes associated with resistance and virulence as discussed in the previous section. The lifestyle of a phage and the presence of potentially dangerous genetic determinants may be analyzed through the use of microbiological techniques by testing their ability to transfer selected markers between bacterial strains, through PCR-based techniques such as testing for the presence of bacterial DNA in phage particles, and through the use of genome sequencing and bioinformatic predictions in order to search for specific sequences associated with gene integration and toxin production [6]. Interestingly, advances in sequencing capabilities and synthetic biology techniques have led to innovative approaches incorporating the use of temperate phages and their lytic variants in phage therapy [178].…”

“…The host range of selected phages must also be considered, with all epidemiologically important strains of a target bacterium being covered, as some bacterial strains contain several serovars which need to be managed [67]. An optimal balance between too narrow of a host range (which could lead to some strains of the same species not being affected) and too broad of a host range (which could lead to the killing of beneficial bacteria present) must be found [6]. While phages used for therapeutic purposes may follow a "personalized medicine" approach, where pathogenic strains are identified within an individual and specific phages are then selected from pre-existing banks for treatment [179], using phage cocktails, where phages of different specificities are utilized in therapeutic applications, is recommended [6].…”

“…The application of bacteriophages within medical, agricultural, and food processing settings provides some of the most promising opportunities for their regulatory approval and commercialization [4,5]. Their ability and potential efficacy to be used against bacteria in both planktonic and biofilm settings provide another reason for their continued examination [6]. Phages continue to be studied as not only bacterial killers, but also as potential active bacterial detectors, and while understanding surrounding them remains relatively limited, computational and bioengineering advancements have the potential to further bolster the utility of the bacterial viruses.…”