Phage therapy: awakening a sleeping giant

Abstract

For a century, bacterial viruses called bacteriophages have been exploited as natural antibacterial agents. However, their medicinal potential has not yet been exploited due to readily available and effective antibiotics. After years of extensive use, both properly and improperly, antibiotic-resistant bacteria are becoming more prominent and represent a worldwide public health threat. Most importantly, new antibiotics are not progressing at the same rate as the emergence of resistance. The therapeutic modality of bacteriophages, called phage therapy, offers a clinical option to combat bacteria associated with diseases. Here, we discuss traditional phage therapy approaches, as well as how synthetic biology has allowed for the creation of designer phages for new clinical applications. To implement these technologies, several key aspects and challenges still need to be addressed, such as narrow spectrum, safety, and bacterial resistance. We will summarize our current understanding of how phage treatment elicits mammalian host immune responses, as well bacterial phage resistance development, and the potential impact each will have on phage therapy effectiveness. We conclude by discussing the need for a paradigm shift on how phage therapy strategies are developed.

Keywords: antibiotic resistance; antibiotics; bacteriophage.

Figure 1.. The bacteriolytic lifecycle of phages.

(Left) Scanning electron microscopy of a bacterial cell (Acinetobacter baumannii, false color) being lysed by phage (vB-GEC_Ab-M-G7) [93] infection. (Right) Phages infect bacteria by first attaching (a) to susceptible cells via specific surface receptors before injecting (b) its viral genome into the cytoplasm. Then, the viral genome hijacks the bacterium whereupon progeny virions are synthesized and assembled. Most phages employ a viral-encoded cell lysis system where holins perforate and weaken the cytoplasmic membrane and endolysins degrade the cell wall peptidoglycan, which then causes the bacterium to violently rupture. Cell lysis can occur within minutes to hours depending on each phage and metabolic status of the bacterium.

Figure 2.. Overview of engineered nonlytic antibacterial phage technologies.

(i) Temperate phage engineered to deliver synthetic gene network (blue) (a), undergo a latent lifecycle after infection, called lysogeny. Here, the viral genome (red) integrates into the bacterium's chromosome as a prophage (b) where it can express antimicrobial proteins (AMPs) that interfere with intracellular processes and cause bacterial death (c). (ii) Phagemids can also deliver synthetic gene network(s) (blue) on a synthetic plasmid (a) that encode for antibacterial proteins, such encoding a RNA-guided CRISPR-associated (Cas) nucleases (b) for sequence-specific (orange) nonlytic bacterial death (c) and plasmid removal (d). Phagemid plasmids can also encode for AMPs (e).