# Phase Therapy: Consider the Past, Embrace the Future
## 2. Phage Therapy  
Phages are viruses that exclusively infect bacteria. They are extremely widespread in nature with the estimated number of approximate \(10^{31}\), far exceeding other microorganisms [14; 15]. What is more, phages play an important role in the regulation of intestinal microbiome, which is of great significance to human health [16]. Like other viruses, phages lack a complete replisome; therefore, the intracellular resources of the invaded cells are necessary for their propagation. Phages are mainly composed of capsid protein and its encapsulated nucleic acid with small volume, simple structure, and strict parasitism. Depending on their lifestyle, phages can be mainly divided into two classes: temperate phages and lytic phages (also known as virulent phages). A complete phage life cycle of the common tailed phage mainly includes the following (Figure 1): first, phages recognize specific receptors and adsorb to the surface of a host bacterium by tail fibers or spikes; then, the phages inject their own genetic material into the host bacteria; next, lytic phages make use of the host bacteria to proliferate and synthesize various components needed by themselves, complete the assembly, and form a large number of progeny phages, finally dissolving a portion of the host cell wall through the specific lysins. The progeny phages are released from the host bacteria and spread, while the host bacteria lyse and die. The lytic phage infection of bacteria is so robust that the lytic phage particle still has a strong lethality after several infection cycles. These properties of lytic phages make some of them particularly effective in treating bacterial diseases. For instance, _Acinetobacter baumaniii_ is a Gram-negative opportunistic pathogen that can be easily spread in the intensive care unit of a hospital [17]. Additionally, most of the clinically isolated _A. baumaniii_ are multidrug-resistant [18], which greatly limits the available treatment options. Some phages have shown the ability to effectively lyse drug-resistant _A. baumaniii_ both in vitro and in vivo [19]. Temperature phages have a choice between the lytic pathway and an alternative lysogenic pathway. In the latter pathway, phages integrate their own genetic material into the host's chromosome, replicate, and co-exist stably with the host bacteria as emphages. There is another type of temperate phage which replicates in bacteria by permanent slow release of progeny without cell lysis, which is designated as permanent infection. These emphages can be maintained in lysogens as plasmids [20; 21]. Certain conditions such as induction with DNA-damaging agents (such as UV radiation and chemicals) will trigger most prophages in a population to re-activate; thus, prophages will stop its dormancy and enter the lytic cycle, further replicating phages and lysing the host [22; 23; 24]. Nonetheless, temperate phages are often not used for phage therapy because they tend not to cause host bacterial lysis until a right condition, and they will prevent subsequent phage entry once a host is infected. Additionally, they are often vectors of horizontal gene transfer, resulting in the transfer of virulent or resistant genes as well as other risks [25; 26]. Phase therapy has some obvious advantages over conventional antibiotics in the treatment of bacterial diseases. Firstly, as a natural antibacterial agent, phages can effectively target Gram-positive and Gram-negative bacteria. At the same time, phages only specifically target their corresponding host, and they do not affect the non-target bacteria; therefore, unlike antibiotics, phages pose no risk of destroying other normal microbiome in the body. Unlike antibiotics inhibiting a single bacterial physiological process, phages affect multiple bacterial physiological processes [12; 27].