Bacteriophage therapy
provide more practical ideas in the pursuit of enduring solutions to the problem of treatment-driven pathogen evolution (e.g., AMR).
These viral parasites of bacterial pathogens are composed of a DNA or RNA genome usually encapsulated by an icosahedral protein capsid head, under which a protein phage tail is attached with distinctive tail fibres and a base plate for their attachment and penetration into the bacterial hosts.
Based on the distinct characteristics of their modes of action, phages can be classified as virulent (lytic) and temperate (lysogenic). Virulent phages are strictly lytic (i.e., they can only enter the lytic cycle), while temperate
Figure 1
The Lytic and Lysogenic Cycles of Bacteriophages
Note. This figure demonstrates the lytic and lysogenic cycles of phages. The life cycle of a phage is either strictly lytic or lysogenic (then lytic). This figure is not covered by the Creative Commons (CC) Attribution 4.0 International License. Reprinted by permission from Springer Nature: Nature Reviews Microbiology, A century of the phage: past, present and future, George P. C. Salmond & Peter C. Fineran (2015), all rights reserved.
phages can enter either the lysogenic or lytic cycle. In both cycles, the initial absorption phase is determined by the complementary attachment between the receptor binding proteins of the phage and the receptor proteins on the bacterial cell membrane, followed by the injection of the phage genome. This step is highly specific, given that the conformation (shape) of the phage’s receptor binding proteins is complementary to that of the bacterial outer membrane receptors of a particular bacterial species, similar to the ‘lock and key’ model. For instance, a specified phage, such as a typical T4 phage, will, almost always, solely be able to bind itself to Escherichia coli. Sometimes, the identified phage may only attach to certain strains of a given bacterial species. The specific binding process gives rise to the unique specificity of phages, which essentially determines the standard procedure required for its therapeutic use. This is a point to which I will return below. After this initial stage of the process, phages’ life cycles start to differ into the two categories shown in Fig. 1. The lytic cycle results in the immediate production of new phage progeny and eventually the direct lysis of bacterial hosts. By contrast, the lysogenic cycle involves the integration of the phage genome into the bacterial DNA in the presence of phage-encoded integrases and, therefore, the phage genome will be passively replicated every time the bacterial host divides unless mobilized under certain conditions. During the lytic cycle, the injected phage genome will be replicated, transcribed (if DNA) and translated by bacterial enzymes, thereby synthesizing the protein and viral lipid components needed for the final assembly. As new virions are formed, the new phage progeny release phage-encoded peptidoglycan hydrolases (aka. endolysins or lysins), which are proteins that are able to disintegrate the bacterial cell wall for new phages to be released. This process is known as lysis, after which the former bacterial host, almost always, dies (with the exception of lysis-deficient phages, which do not result in immediate cell lysis but will still cause the eventual death of bacterial hosts). 29
29 Matsuda et al. 2005.
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